WELCOME TO ALL OF YOU WHO HAVE
REGISTERED AND NOW ARE
ATTENDING THIS REALLY VERY,
VERY EXCITING WORKSHOP ON
CURRENT AND FUTURE RESEARCH
DIRECTIONS IN CYSTIC FIBROSIS.
JIM KILEY, AHEAD OF THE LUNG
DIVISION AT NDI AND IT IS
REALLY A PLEASURE TO WELCOME
YOU TO THIS WEBSITE.
IT IS SUCH A PLEASURE TO BRING
TOGETHER SUCH A GROUP OF
PEOPLE, YOU MAY KNOW WE HAVE
500 REGISTERED FOR THIS
MEETING SO I THINK WE HIT THE
NAIL ON THE HEAD WITH THE
TOPIC AND INTEREST ON BEHALF
OF THE COMMUNITY AND WE'RE
REALLY LOOKING FORWARD TO SOME
VERY EXCITING PRESENTATIONS,
DISCUSSIONS AND THEN
RECOMMENDATIONS FROM ALL OF
YOU IN TERMS OF THE DIRECTIONS
WE NEED TO GO IN THIS FIELD.
SO I AM GOING TO DO SOMETHING
A LITTLE BIT OPPOSITE THAN
USUALLY YOU DO WITH WELCOMES
BY JUST SAYING HELLO TO ALL OF
YOU, TO REALLY EXTEND A VERY
SPECIAL, SPECIAL THANKS TO ALL
OF THE PEOPLE WHO HAVE WORKED
TIRELESSLY TO PUT THIS
ALTOGETHER AND THIS IS A
OUTSTANDING AGENDA WITH SOME
WONDERFUL SPEAKERS.
WE HAVE ALL THE EXPERTS REALLY
IN THIS FIELD WITH US AND I
THINK THIS IS GOING TO BE
QUITE AN EXCITING COUPLE OF
DAYS.
I HAVE TO EXTEND A SPECIAL
THANKS TO OUR COCHAIRS SO THAT
INCLUDES DOCTORS INGLEHARDT,
BURKETTE AND OTHER SPEAKERS
FOR NOT ONLY HELPING WITH THE
AGENDA BUT THE TIME THEY PUT
INTO THIS WHICH IS NOT A SMALL
TASK SO WE THANK THEM FOR
DEVOTING TIME TO IT AND
JOINING US WITH THE WORK ON
THIS SPECIAL WORKSHOP.
I ALSO WANT TO EXTEND A THANKS
TO THE CYSTIC FIBROSIS
FOUNDATION, Dr. CLANCY, I
KNOW YOU ARE HERE SOMEWHERE,
Dr. ROWE, THANK YOU FOR ALL
YOUR HELP WITH THIS AND
PARTNERSHIP OVER THE YEARS AS
WE HAVE HAD SUCH A
LONGSTANDING RELATIONSHIP WITH
THE CF FOUNDATION AND HOPE TO
BUILD OFF OF THAT GOING
FORWARD.
ONE OF THE THINGS YOU HAVE
NOTICED RIGHT AWAY IS THIS IS
A TOPIC OF INTEREST TO SEVERAL
INSTITUTES AT THE NIH AND I
HAVE TO SAY OUR COMMITTEE
INCLUDES Dr. EGGERMAN FROM
NAIAD AND OTHERS DONE A LOT OF
THE HEAVY LIFTING TO BRING
THIS ALTOGETHER WITH THE
AGENDA WE HAVE TODAY.
SO I AM REALLY THANKFUL TO ALL
OF YOU, FOR THE LONDON
DIVISION AND ALSO AT THE NHAI,
WELCOME TO THIS WONDERFUL
TOPIC.
LET ME MOVE ALONG SINCE WE
HAVE A PACKED AGENDA, BUT ONE
OF THE THINGS WE IDENTIFIED
FOR TOMORROW IN WATCHING THE
SCIENCE AND THE LANDSCAPE AND
REALLY HELPING TO IDENTIFY
DIRECTIONS, PUT TOGETHER A
WORKING GROUP THAT INCLUDED
ALL OF YOU AND OUR SISTER
AGENCY AT THE INSTITUTES AT
NIH.
WHEN WE REALIZED THERE WAS A
PRETTY GOOD SEA CHANGE IN THE
RESEARCH LANDSCAPE AFTER THE
APPROVAL OF TRICAPTA BY THE
FDA IN 2013 SO THAT MEANT WE
REALLY NEEDED TO REASSESS WITH
ALL OF YOU WITH THE EXPERTS IN
THE FIELD TO ADDRESS THE
CRITICAL QUESTIONS THAT WE
FORM THE FIELD FOR FUTURE
RESEARCH AS WE MOVE FORWARD
AND LOOK AT THESE HIGHLY
EFFECTIVE MODULATED THERAPIES
FOR TREATMENT OF CF.
AND I THINK THIS IS A TIME FOR
US TO REALLY TAKE STOCK IN
WHERE WE HAVE BEEN, WHERE WE
ARE TODAY AFTER SOME MAJOR,
MAJOR ADVANCES AND TO BRING
TOGETHER THIS PANEL'S EXPERT
AND COMMITTEE, LOOKING WITH
THE PWA*ED OF SCIENCE THAT
NEEDS TO ADDRESS THE PROBLEM
FROM BASIC TRANSLATION WITH
CLINICAL BACKGROUND AND REALLY
LOOK AT CRITICAL QUESTIONS IN
GAPS AND OPPORTUNITIES THAT
NEED TO BE ADDRESSED GOING
FORWARD.
SO THAT BASICALLY SETS THE
STAGE FOR THIS WORKSHOP AND
THE GOAL IS TO HIGHLIGHT THE
CHALLENGES AND OPPORTUNITIES
FOR RESEARCH IN THE CONTEXT OF
THIS RAPIDLY SHIFTING
TREATMENT OPTIONS FOR ALL
PEOPLE WITH CYSTIC FIBROSIS
INCLUDING THOSE NOT CREDIBLY
ELIGIBLE FOR THE VARIETY OF
MODULATED THEIRS THAT EXIST
TODAY.
SO WE WILL GIVE PERSPECTIVES
OF INDIVIDUALS WITH CF, SOME
OF THE CAREGIVERS, SOME WILL
SPEAK ON THE THERAPY WHO ARE
NOT ELIGIBLE AND BOTH
PERSPECTIVES WILL HELP US
UNDERSTAND WHAT RESEARCH IS
NEEDED TO ADDRESS FUTURE
CRITICAL CLINICAL CARE FOR ALL
PEOPLE WITH CF.
SO IT IS A BROAD-RANGING
AGENDA, INVOLVES WHAT WE THINK
ARE THE KEY STAKEHOLDERS AND
REALLY DESIGNED TO GIVE US A
LITTLE BIT OF A BLUEPRINT OR
ROAD MAP, AT LEAST THE SENSE
OF WHERE THE MOST CRITICAL
QUESTIONS ARE THAT COULD BE
IMPACTFUL AS WE MOVE PAST OUR
CURRENT STATE OF KNOWLEDGE AND
UNDERSTANDING OF THIS DISEASE
BOTH FROM A MECHANISTIC
PATHOBIOLOGY, GENETIC AND ALL
THE WAY UP TO HOW DO WE
IMPLEMENT IN THE POPULATION
THAT WE'RE TESTING.
SO I HOPE ALL OF YOU CAN
REALLY FOCUS ON THAT.
I KNOW THESE WORKSHOPS TEND TO
BE A CATCH-ALL SO YOU OFTEN
WILL COME UP WITH A LAUNDRY
LIST AT THE END OF SOMEWHERE
AROUND 15, 20 OPPORTUNITIES,
GAPS, RESEARCH DIRECTIONS, BUT
TRY TO GIVE SOME THOUGHT TO
PRIORITIZATION A BIT.
WHAT I LIKE TO LEAVE PEOPLE
WITH IS WHAT ARE THE REALLY
HIGHEST IMPLEMENTABLE AREAS WE
NEED TO FOCUS ON THAT WILL
REALLY HAVE AN IMPACT AND MAKE
A DIFFERENCE AND NOT BE JUST
INCREMENTAL BUT ADVANCE OUR
SCIENCE IN A SUBSTANTIVE
WAIVE.
SO THINK ABOUT IT IN THOSE
TERMS.
THE GOAL OF THIS WORKSHOP WILL
BE A PUBLICATION THAT I KNOW
WILL BE EXCITING AND IMPORTANT
IN SETTING THE STAGE WHERE WE
ARE AND OUR UNDERSTANDING OF
THE SCIENCE TO DATE BUT ALSO I
HOPE WILL GIVE THE COMMUNITY A
SENSE OF DIRECTION, WHERE WE
NEED TO FOCUS OUR RESEARCH
EFFORTS.
WHEN WE DO THESE WORKSHOPS IN
PERSON, WE HAVE 30, 40, 50
PEOPLE IN THE ROOM AND
OFTENTIMES YOU CAN'T GET THE
WORD OUT TO EVERYONE ABOUT
WHAT YOU HAVE RECOMMENDED OR
SUGGESTED IN TERMS OF RESEARCH
DIRECTION.
WHEN WE DO THE VIRTUAL ONES,
WE HAVE EVERYBODY, FOUR, 500
PEOPLE TO HEAR THE
RECOMMENDATIONS AND THAT IS AN
INVITATION TO EVERYONE TO
THINK NOT WAIT FOR
SOLICITATIONS BUT THINK ABOUT
THE NEXT STEPS AND YOU CAN
THINK ABOUT THE NEXT STEPS ON
YOUR OWN AND THAT WE ARE OPEN
FOR BUSINESS.
THE ROBUST MECHANISM IS THERE
FOR EVERYONE TO SUBMIT
APPLICATIONS ACROSS NIH AND
WE'RE VERY INTERESTED IN
RECEIVING THOSE APPLICATIONS
FROM YOU.
SO I WILL STOP THERE AND TURN
IT BACK TO I THINK MARRAH AND
AGAIN, I WELCOME ALL OF YOU,
THANK YOU FOR YOUR TIME AND
ATTENTION AND I LOOK FORWARD
TO HEARING SOME OF THE
DISCUSSIONS OVER THE NEXT
COUPLE OF DAYS AND OUTPUT FROM
THIS WORKSHOP SO THANK YOU ALL
VERY MUCH AGAIN.
>> THANK YOU Dr. KILEY FOR
THAT TERRIFIC INTRODUCTION AND
START TO THIS WORKSHOP.
GOOD MORNING.
FOR THOSE WHO DON'T KNOW ME, I
AM MARRAH LACHOWICZ-SCROGGINS,
I AM THE PROGRAM DIRECTOR AT
AIRWAY BIOLOGY DISEASE BRANCH
AND IT IS MY PLEASURE TO
WELCOME YOU TO THIS WORKSHOP.
NEXT SLIDE.
SO AS Dr. KILEY MENTIONED,
WE ARE HERE TO BRING TOGETHER
SUBJECT MATTER EXPERTS FROM
THE CLOSE COMMUNITY TO DISCUSS
NEEDS FOR RESEARCH IN THE AREA
OF HIGHLY EFFECTIVE MODULATOR
THERAPIES.
WE HAVE ASSEMBLED A DIVERSE
TEAM OF RESEARCHERS, CARE
PROVIDERS AND ADDRESS GAPS IN
RESEARCH AND CLINICAL CARE FOR
PEOPLE WITH CF.
WE ASKED FOR YOUR HELP AS
SUBJECT MATTER EXPERTS TO
SHIFT THE FOCUS TOWARDS THE
UNDERSTANDING OF THE CLINICAL
COURSE WE UNDERSTAND IN THIS
ERA FOR INDIVIDUALS WITH CF.
FOR THOSE WHO ARE ELIGIBLE FOR
MODULATOR THEIRS AND FOR THOSE
WHO ARE NOT SO WE WANTED TO
ADDRESS GAPS IN CARE INCLUDING
HEALTH EQUITY AND SPECIAL
POPULATIONS.
WE'RE LOOKING FOR YOUR
KNOWLEDGE TO MOVE THIS FIELD
FORWARD THE NEXT FIVE TO TEN
YEARS.
WITH THAT, I HOPE THIS GROUP
WILL MOVE FORWARD WITH
COLLABORATION AND BE BOLD IN
THE IDEAS THAT YOU SHARE
TODAY.
NEXT.
I WILL BRIEFLY EXPLAIN SOME OF
OUR MEETING LOGISTICS.
THIS MEETING IS BEING
RECORDED.
SOME RESEARCHERS MAY SHARE
CONFIDENTIAL DATA SO WE ASK
YOU MAINTAIN INTEGRITY AND
CONFIDENTIALITY IN THE
WORKSHOP.
WE ASK YOU USE THE CHAT IF YOU
NEED TECHNICAL QUESTIONS AND
TO REGISTER YOUR QUESTION.
AS YOU ENTER THIS MEETING AND
WORKSHOP, YOU ARE OFF CAMERA
AND WE ASK YOU STAY THAT WAY
TO INCREASE BANDWIDTH.
YOU CAN COME OFF AT THE END OF
THE DAY WITH MODERATORS TO
FACILITATE DISCUSSION AND
COLLABORATION.
NEXT SLIDE.
WE ALSO HAVE A PROGRAM BOOK
FOR THIS WORKSHOP WHICH WILL
HAVE THE SPEAKER BIOS AND
MATERIALS.
TO STAY ON TIME, WE ASK YOU
USE THIS RESOURCE AS SESSION
MODERATORS WILL NOT GIVE FULL
BIOS DURING THE SESSION.
FOR THE ORGANIZATION OF THIS
WORKSHOP, WE WILL HAVE
15-MINUTE BACK-TO-BACK
PRESENTATIONS FOLLOWED BY A
DEDICATED Q&A FOR EACH
SESSION.
AGAIN, PLEASE USE THE CHAT
TOOL FOR THE QUESTIONS YOU
WANT DIRECTED TO THAT SESSION.
LATER IN THE DAY, WE WILL HAVE
THREE BREAKOUT SESSIONS AND
THESE WILL OCCUR
SIMULTANEOUSLY.
THESE BREAKOUTS WILL BE
DESIGNED BY A TAN PANEL AND
ARE DESIGNED TO BE BREAKOUTS
WHERE WE WELCOME YOUR
CONVERSATION AND DISCUSSION.
YOU CAN USE ALL THE TOOLS LIKE
HAND RAISE AND HOPE YOU WILL
BE FULLY ENGAGED IN THE
BREAKOUT GROUPS.
IF YOU HAVE ANY ISSUES WITH
THE BREAKOUT SESSIONS, YOU CAN
ALWAYS COME BACK TO THE MAIN
MEETING ROOM AND ASK FOR
ASSISTANCE.
NEXT SLIDE.
AS I SAID, WE'LL FREQUENTLY
POST THE AGENDA AND PROGRAM
BOOK IN THE CHAT AS A RESOURCE
FOR THE WORKSHOP PARTICIPANTS
AND FOR THE STRUCTURE OF
TODAY, WE WILL HAVE THREE
SESSIONS.
OUR FIRST SESSION IS A PLENARY
HOSTED BY THE CYSTIC FIBROSIS
FOUNDATION.
THIS SETS THE STAGE FOR THE
WORKSHOP TO LET YOU KNOW WHERE
WE ARE IN THE LANDSCAPE AND
HIGHLY EFFECTIVE MODULATOR
THEIRS.
AS Dr. KILEY SAID, WE WILL
SEE WHERE WE HAVE BEEN, WHERE
WE ARE AND WHERE WE ARE GOING.
WE ALSO WILL HEAR ABOUT
CLINICAL TRIALS FOR THE
MODULATOR THEIRS.
WE WILL HAVE ANIMAL MODEL
SYSTEMS TO UNDERSTAND THE
CLINICAL COURSE AND HOW WE CAN
USE THESE FOR RESEARCH
OPPORTUNITIES.
SESSION 2 WILL DISCUSS
LATE-STAGE CYSTIC FIBROSIS
PATHOGENESIS AND PROCESSES.
WE WILL HAVE THE BREAKOUT
SESSIONS FOLLOWED BY A REGROUP
AND REPORT OUT BY THE DAY 1
PANELISTS.
NEXT SLIDE.
AS WE HAVE ALREADY SAID
SEVERAL TIMES THIS MORNING, WE
REALLY DO WANT TO HEAR FROM
YOU.
WE HAVE THESE BREAKOUTS
DESIGNED FOR YOUR
PARTICIPATION BUT YOU CAN ALSO
SEND YOUR THOUGHTS USING THE
MEETING HASHTAG, OR YOU CAN
E-MAIL US DIRECTLY FOR
COMMENTS, IDEAS AND FEEDBACK.
WE WILL POST THIS INFORMATION
IN THE CHAT THROUGHOUT THE
WORKSHOP.
NEXT SLIDE.
NOW, I KNOW Dr. KILEY
ALREADY GAVE ACKNOWLEDGEMENTS
BUT I WANTED TO SEND ANOTHER
HUGE THANKS TO THE WORKSHOP
PLANNING TEAM, CO-CHAIR, ALL
OF OUR SPEAKERS AND BREAKOUT
MODERATORS.
THEY HAVE PUT A LOT OF TIME
AND EFFORT IN PLANNING THIS
EVENT AND VERY MUCH LOOK
FORWARD TO WHAT WE HAVE IN
STORE THE NEXT TWO DAYS.
FINALLY THIS WORKSHOP WOULD
NOT BE POSSIBLE WITHOUT THE
SUPPORT OF OUR SUPPORT GROUP
AND OUR TECHNICAL TEAM MEMBERS
WHO HAVE BEEN NOTHING SHORT OF
AMAZING.
WITH THAT, I WOULD LIKE TO
THANK YOU ALL FOR REGISTERING
AND I WILL TURN OVER THE FLOOR
TO Dr. CLANCY FROM THE
CYSTIC FIBROSIS FOUNDATION TO
KICK OFF OUR SESSION.
>> HELLO EVERYONE, THANK YOU,
MARRAH, VERY EXCITED TO KICK
THIS OFF, I AM Dr. CLANCY,
VICE PRESIDENT OF CLINICAL
RESEARCH WITH THE CYSTIC
FIBROSIS FOUNDATION, THANK YOU
FOR ADVANCING THAT NEXT SLIDE,
SO I WANT TO TALK ABOUT OUR
RESEARCH AND HOW THE FIELD IS
CHANGING.
I WILL BE KICKING THINGS OFF
FOLLOWED BY A PRESENTATION BY
STEVE ROWE WHO IS AT THE
CYSTIC FIBROSIS AND GIVING US
A GLIMPSE OF THE FUTURE
DIRECTIONS AND THEN WE HAVE AN
ASSOCIATE PROFESSOR AT
UNIVERSITY CAMPUS MEDICAL
CENTER AND WE WILL BE FOCUSING
ON SOME OF THOSE FINDINGS AND
CLINICAL TRIALS OF HIGHLY
EFFECTIVE MODULATORS AND THEN
WE WILL COMPLETE THE
PERSPECTIVE WITH MELANIE WHO
HAS BEEN A KEY PARTNER IN THIS
RESEARCH AS WELL AS A VOICE IN
THE COMMUNITY TO HELP EDUCATE
US AS RESEARCHERS --
[INDISCERNIBLE]
WE WILL THEN HAVE A Q&A
SESSION AND THAT WILL COMPLETE
OUR FIRST SESSION.
THANK YOU.
SO NEXT SLIDE, PLEASE.
JUST A QUICK 'TIS CLOSURE THAT
THE CF FOUNDATION DOES INVEST
IN EARLY DRUG DEVELOPMENT AND
IF THOSE INVESTMENTS LEAD TO
PRODUCTS THAT MAKE IT TO THE
MARKET AFTER APPROVAL IN SOME
MARKETS, YOU CAN RECEIVE FUNDS
BACK TO THE CF FOUNDATION AND
WE HAVE MORE INFORMATION IF
YOU WOULD LIKE TO HEAR ABOUT
THAT ON OUR CF WEBSITE.
NEXT SLIDE.
SO I WILL KICK US OFF TALKING
A LITTLE BIT ABOUT THE
RESEARCH IMPACT TODAY AND
HIGHLY EFFECTIVE MODULATORS,
STEVE WILL TALK ABOUT THE
FOUNDATION RESEARCH PRIORITIES
GOING FORWARD INCLUDING
SYMPTOMATIC THEIRS, PTA C AND
LOOKING AT MEDICATION.
NEXT SLIDE.
THIS IS A SLIDE THAT IS NOT
SURPRISING OR NEW TO ANYONE
BUT REALLY TO HELP US REMEMBER
THE STEPS THAT ARE INVOLVED
BETWEEN THE CFTR GENE DEFECT
WHICH LEADS TO THE CFTR
PROTEIN DEFECT AND DEHYDRATED
AIRWAY SURFACES.
I HAVE HIGHLIGHTED THE LUNGS
HERE AND THESE ABNORMALITIES
AFFECT MANY ASPECTS OF LIFE
WITH PEOPLE WITH CF.
THE MUCOUS BUILDUP AND
INFECTION THAT LEADS TO
INFLAMMATION AND PROGRESSION
OF THE DISEASE.
IT IS PROGRESSIVE, NEXT SLIDE.
AND WHAT WE HAVE LEARNED WITH
THE MODULATORS THAT ADDRESS AN
UPSTREAM TARGET IN THIS
CASCADE REALLY HAVE AMAZING
EFFECTS AND ARE HIGHLY
EFFECTIVE.
YOU CAN ADVANCE.
AND SPECIFICALLY THE HIGH LIE
EFFECTIVE MODULATORS ARE DRUGS
WHICH REALLY HAVE A DRAMATIC
EFFECT ACROSS A VARIETY OF
EFFECTS SUCH AS LUNG FUNCTION,
APEX, SYMPTOMS, WEIGHT,
MICROBIOLOGY, TRANSPLANT AND
SURVIVAL.
THE TESTED THEIRS INCLUDING
ALL THESE BENEFITS ARE
MANIFEST AND REALLY HELP US
FIND THE EFFECTIVE THEIRS.
NEXT SLIDE.
SO WITH THAT, BASED ON THIS
TYPE OF INFORMATION, IT IS
ESTIMATED APPROXIMATELY
93 PERCENT OF PEOPLE WITH CF
SHOULD POTENTIALLY BECOME
CANDIDATES FOR MODULATORS.
THAT IS OBVIOUSLY BASED ON AGE
AND APPROVALS AND NOT EVERYONE
CAN BENEFIT FROM MODULATORS
BUT WE KNOW THEY HAVE SHIFTED
THE LANDSCAPE DRAMATICALLY AND
RENDER HIGHLY EFFECTIVE
THERAPY TO PEOPLE WITH CF AT
YOUNGER AND YOUNGER AGES.
IT DOES RAISE THE QUESTION, IS
THE CF RESEARCH OVER?
AND NEXT SLIDE.
I HOPE I CAN LAY THE GROUND
WORK THAT THIS IS NOT THE CASE
AND IN FACT IS ABSOLUTELY NOT
THE CASE.
I WOULD SAY THAT CF HAS
FUNDAMENTALLY CHANGED AND WE
KNOW THERE ARE NUMEROUS VERY,
VERY BASIC QUESTIONS THAT NEED
TO BE ANSWERED FOR US TO
REALLY BE ABLE TO UNDERSTAND
MODULATORS AND UNDERSTAND
THEIR BENEFITS AND ALSO THE
ROLE OF OTHER THEIRS.
AS AN EXAMPLE, NO SYMPTOMATIC
CF THEY WERE HAS EVER BEEN
STUDIED IN CF IN THE CONTEXT
OF FUNCTIONAL CFTR.
WHAT IS THE LIFE COURSE OF
LUNG DISEASE, WHAT ASPECTS ARE
REVERSIBLE AND NOT
RESERIOUSABLE?
WHY IS THE VAPOR INDIVIDUAL
BENEFIT AND TOLERANCE?
WHAT IS THE IMPACT ON
INFECTION AND WHAT IS THE ROLE
OF SYMPTOMATIC THEIRS?
ALL OF THOSE QUESTIONS AND YOU
WILL HEAR MORE INDEPTH
QUESTIONS THROUGHOUT THIS
MEETING AND THAT IS ULTIMATELY
OUR GOAL, TO IDENTIFY THOSE
QUESTIONS BUT I ALSO WANTED TO
HIGHLIGHT THE CF FOUNDATION
REMAINS ABSOLUTELY COMMITTED
TO CURE THEIRS FOR PERSONS
WITH CF.
SO LOOKING AT THE NUMBERS OF
PERSONS WITH CF, THE GREEN
BEING PEDIATRIC PATIENTS AND
THE BLUE ARE ADULT DISEASE AND
OVER 30 YEARS TO TODAY, YOU
CAN SEE CF HAS FUNDAMENTALLY
CHANGED.
THE DEMOGRAPHICS ARE
FUNDAMENTALLY DIFFERENT.
IT WAS PREDOMINANTLY PEDIATRIC
DISEASE YEARS AGO, NOW IT IS
AN ADULT DISEASE.
NEXT SLIDE.
YOU CAN ADVANCE ONE MORE.
LOOKING AT THAT DATA -- OR
MOVING FROM THAT DATA TO THE
FUTURE, ESTIMATES OF PEOPLE
ARE CF IN THE PEDIATRIC GROUP
UNDER AGE 18 AND IN THE LIGHT,
THE ADULTS AND WHAT WE HAVE
SEEN IS A FIVE-YEAR MARCH
FORWARD, THIS SLIDE WAS PUT
TOGETHER IN 2016 BUT I THINK
IT IS STILL TRUE TODAY.
IF YOU LOOK ON THE LEFT GROUP,
5 YEARS, 10 YEARS, WE DON'T
SEE A DIFFERENCE BUT WE SEE A
SIGNIFICANT IMPROVEMENT AS
TIME GOES BY AND MODULATORS
BECOME AVAILABLE FOR
PEDIATRICS.
WHAT WE SEE IS THOSE WITH
NORMAL LUNG FUNCTION AND THE
REDUCTION OF PATIENTS WHO HAVE
MODERATOR EXPERIENCE.
ON THE RIGHT SIDE, WE'RE
LOOKING AT THE ADULT
POPULATION AND I THINK THE
TAKEHOME POINT HERE IS IT IS
GOING TO GROW, THE NUMBER OF
PEOPLE SURVIVING WITH CF AND
THE NUMBER OF ADULTS WILL GET
LARGER AND BE A 40 TO
50 PERCENT INCREASE IN THE
NUMBER OF ADULTS WITH CF OVER
THE NEXT 20 YEARS.
AND THE OTHER POINT I WANTED
TO MAKE IS PEOPLE WITH CF ARE
GOING TO HAVE LUNG DISEASE.
CERTAINLY THE NUMBER WITHOUT
LUNG DISEASE OR LOW LUNG
DISEASE WILL GROW BUT THOSE
WITH MODERATE OR ADVANCED LUNG
DISEASE NEED OUR CARE AND IN
FACT WE SEE THAT AS A GROWING
NEED OVER THE NEXT 10 TO 20
YEARS.
NEXT SLIDE.
SO THERE ARE A NUMBER OF
SLIDES FUNDED BY OUR
FOUNDATION.
I WILL NOT SPEND TIME WITH ALL
OF THESE AS WE WILL HEAR FROM
THEM LATER ON BUT TRYING TO
UNDERSTAND THE ASPECTS IN THE
CONTEXT OF MODULATOR USE
LOOKING AT SYMPTOMOTOLOGY
CARE, THE MEASURE OF OUTCOME
INDICATORS, DECENTRALIZED
STUDIES REGARDING WHAT PEOPLE
ARE DOING ON THEIR OWN UNDER
THE CONTEXT OF CARE AND THE
IMPACT OF PREGNANCY.
WE ACKNOWLEDGE AS MANY AS A
QUARTER OF THE POPULATION IN
THE U.S. MAY BE PARTICIPATING
IN THESE STUDIES IN ONE WAY OR
THE OTHER.
NEXT SLIDE.
SORRY, THAT WAS A LEFTOVER, IF
YOU COULD MOVE FORWARD THE
SLIDES.
MY APOLOGIES.
BUT I WANTED TO HIGHLIGHT
WHERE RESEARCH FUNDS ARE BEING
SPENT CURRENTLY AND THIS IS
LOOKING AT OUR 2021 BUDGET,
LOOKING AT MEDICAL AND
RESEARCH ON THE TOP RIGHT AND
THEN RESEARCH DOWN BELOW WHICH
IS BROKEN DOWN IN THE
DIFFERENT TOPIC AREAS HERE AND
THE CF FOUNDATION IS FUNDING A
LOT OF THESE ASPECTS AND YOU
CAN SEE THE CURRENT CFTR
MODULATORS ALONG WITH THE
OTHER ASPECT TENDS TO BE THE
LARGEST BECAUSE OF THE IMPACT
AND WE CAN SEE BELOW THE
CLINICAL RESEARCH SUPPORT.
NEXT SLIDE.
BUT I ALSO WANT TO EMPHASIZE
IT GOES BEYOND RESEARCH.
NEXT SLIDE.
OUR MISSION REALLY CUTS ACROSS
WHAT WE CALL THE THREE C'S,
CURE, CARE OF THE PATIENTS AND
THE COMMUNITY AND YOU CAN SEE
UNDER EACH OF THESE AREAS THAT
THE CF FOUNDATION SUPPORTS,
SIGNIFICANT ACTIVITY.
THE CURE IS VERY INVOLVED IN
INDUSTRY PROGRAMS AND ALSO
INVESTIGATOR-INITIATED
RESEARCH.
CARE IS FOCUSED ON PROVIDING
SUPPORT CARE CENTERS, CFF
REGISTRY AND ON THE RIGHT,
PATIENT SUPPORT GROUPS AND
ADVOCACY.
ADVANCE.
BUT I ALSO WANT TO HIGHLIGHT
THE INVESTIGATOR-INITIATED
RESEARCH IS A CLEAR
OPPORTUNITY FOR US TO BE
FUNDED BY NIH AND REALLY
IMPACT ALL THREE ASPECTS OF
PEOPLE WITH CF.
SO I WOULD LIKE TO ADVANCE AND
TURN THE SPOTLIGHT OF THE
MICROPHONE OVER TO MY
COLLEAGUE STEVE ROWE WHO WILL
BE TAKING A LOOK FORWARD AT
THE FUTURE OF CF PRIORITIES.
ARE YOU READY?
>> YES, THANK YOU VERY MUCH,
Dr. CLANCY, HAPPY TO JOIN
YOU.
I ALSO WANT TO CONGRATULATE
THE NIH AND PARTNERS NIAD FOR
HOSTING THIS.
IT IS REALLY A PERFECT TIME TO
LOOK AT PEOPLE WITH CF AND
WHAT THE RESEARCH PRIORITIES
SHOULD BE FOR THE FUTURE.
IN THE TRANSITION PERIOD, I
WANT TO THANK Dr. CLANCY AND
OTHERS FOR PUTTING TOGETHER
THE MATERIALS FOR THIS.
THE PURPOSE IS TO GIVE A HIGH
OVERVIEW OF THE THERAPEUTIC
LANDSCAPE AND I LOOK FORWARD
TO LEARNING FROM ALL OF YOU AS
WE CONSIDER THE RESEARCH
PRIORITIES GOING FORWARD.
HOPEFULLY I WILL PLANNED SOME
SEED HERE AND LET IT GROW
THROUGH THIS GREAT SYMPOSIA WE
HAVE TODAY.
NEXT SLIDE.
SO IT IS CONSIDERED DRUG
DEVELOPMENT IN THE HIGHLY
EFFECTIVE MODULATOR ERA, THERE
ARE OBVIOUSLY SYMPTOMATIC
THEIRS THAT WILL CONTINUE TO
BE IMPORTANT AS WELL AS
THERAPEUTICS DRIVEN TOWARDS
CORRECTING CFPR, BOTH GENETIC
AND THE MODULATOR THEIRS WE
KNOW ABOUT THAT HAVE BROUGHT A
BROAD *EUFRP TUGS FOR
ASSESSMENT.
AND I THINK IT IS BEEN POINTED
OUT HOW THIS GROUP OF PATIENTS
IS GROWING AND HOW THEY NEED
TO HAVE SOME LOW DISEASE
PROGRESSION THAT INVOLVES OVER
TIME AND THESE SYMPTOMATIC
THEIRS WILL BE MORE IMPORTANT
TO THAT POPULATION AS IT GROWS
INCLUDING ANTI-INEFFECTIVES,
MUCOLYTICS, HIDE DATERS,
ANTI-INFLAMMATORIES AND GI AND
NUTRITIONAL NEEDS.
AND TO FIGURE OUT HOW MUCH
THEY NEED AND WHEN THEY NEED
IT WILL BE A MAJOR PRIORITY.
NEXT SLIDE.
IF WE LOOK AT THE DRUG
DEVELOPMENT PIPELINE, YOU CAN
SEE THIS LANDSCAPE OF THEIRS
THAT ARE IN DEVELOPMENT, THE
APPROVED THEIRS ARE ON TOP OF
IT.
THOSE IN DEVELOPMENT REMAIN
QUITE ROBUST WHICH IS EXCITED
TO THINK ABOUT, BRINGING
THERAPIES NEEDED FOR THIS
GROWING GROUP OF INDIVIDUALS
BUT NOT WITHOUT CHALLENGES TO
SUCCESSFULLY DEVELOP THESE
DRUGS AND FIGURE OUT THE RIGHT
PEOPLE WITH CF WHICH CAN
PARTICIPATE AND THE BEST
CANDIDATES TO ASSESS THESE
THEIRS.
THERAPIES.
IN PURPLE, THERE ARE MORE
ADVANCED STAGES WITH TRIALS
ONGOING AND TO HIGHLIGHT SOME
OF THE TRIALS IN EARLY
DEVELOPMENT OR IN THE STARTUP
PHASE THROUGHOUT THE TALK.
THERE'S ALSO THEIRS IN THE
SYMPTOMATIC GROUPS AS WELL AS
ANTI-INFLAMMATORY IN GREEN AND
BLUE THAT ARE RESPECTIVELY
ADVANCING.
THE INFECTION RESEARCH
INITIATIVE WHICH I WILL
HIGHLIGHT IN THE SLIDE GOING
FORWARD IS EXTENSIVE AND
INCLUDES A NUMBER OF ANT
FIVECROBIALS THAT CAN ADDRESS
THE INFECTION THAT PEOPLE HAVE
AND MOST LIKELY DEAL WITH THE
SEVERITY OF THE DISEASE AS IT
ADVANCES EVEN IN THE CONTEXT
OF HIGHLY EFFECTIVE MODULATOR
THERAPY.
EVEN NUTRITIONAL THERAPY AS
WELL.
NEXT SLIDE.
SO AS WE LOOK AT THE LARGE AND
GROWING POPULATION OF ADULTS
WITH LUNG DISEASE, IT IS
UNCLEAR EXACTLY WHO NEEDS
WHAT.
SO HOW DO WE DEVELOP NEW
THERAPIES FOR THESE SUBPOPULAT.
AND ENROLL THE HIGHLY
EFFECTIVE AND NONE HIGHLY
EFFECTIVE MODULATOR SUBJECTS
AND WHAT IS THE REGULATORY
PATH.
ALSO STUDIES INCLUDE THE CF
AND NONCF SUBJECTS AND THEN
THERE ARE PATIENTS IN WHICH
DOSING IS NOT APPLICABLE AND
THIS WILL BE A URGENT NEED TO
APPROVE.
IF ANYTHING, THIS POPULATION
HAS ONLY INCREASED WITH THE
DEVELOPMENT OF MODULATOR
THERAPY FOR OTHERS.
SO WHAT WE REALLY NEED TO DO
IS DEFINE WHO NEEDS WHICH
THERAPIES AND HOW WE DEVELOP
THEM IN THE SUBPOPULATION.
WE NEED TO FIND PATIENTS WHO
ARE CONTINUING TO PROGRESS AND
THEN CONSIDER WHETHER WE WANT
TO ENROLL PATIENTS WHO ARE ON
AND OFF HIGHLY EFFECTIVE
MODULATOR THERAPY, SHOULD THEY
BE SEPARATED?
I THINK IT WILL DEPEND ON THE
SOURCE OF THEIRS BEING
DEVELOPED, BUT THAT WILL BE A
KEY QUESTION OF WHAT WILL THE
APPROACHING FOR THESE
PATIENTS.
CAN WE HELP FACILITATE THAT
FOR THESE PATIENTS WITH URGENT
NEED.
STUDIES INCLUDING CF AND NONCF
SUBJECTS ARE ON THE HORIZON AS
THEY BECOME MORE SIMILAR WITH
PATIENTS WHO HAVE PARTIAL
DYSFUNCTION, AND HOW THEY ARE
SIMILAR TO MANY PATIENTS WITH
CF THAT IS CAUSED BY
PARTIAL CF DYSFUNCTION, AS A
EXAMPLE.
AND THEN -- PEOPLE WITH CF AND
BEYOND WILL BE A PRIORITY.
NEXT SLIDE.
NOW TO HIGH LIE LIGHT THE
INFECTION RESEARCH INITIATIVE,
ESTABLISHED IN 2018 AND IT
CAME FROM THE COMMUNITY AFTER
A LARGE SURVEY BOTH OF
PROVIDERS AND PATIENTS WITH
FAMILIES WHO IDENTIFIED
CONTINUED PROBLEMS WITH
INFECTION AND EVEN AS THAT
TIME IN THE EARLY DAYS OF THE
CF MODULATOR THERAPY WAS OF
CONCERN SO TO ADDRESS THIS,
THERE WAS A LARGE FINANCIAL
COMMITMENT AND IT IS LIKELY
THIS INITIATIVE WILL CONTINUE
FOR SOMETIME.
WE'RE GOING TO NEED EFFORTS TO
IMPROVE DETECTION AND
DIAGNOSIS.
THIS IS ONLY BECOME MORE ACUTE
AS SOME PATIENTS HAVE LESS
OBVIOUS EXPECTORATION SO HOW
DO WE IDENTIFY DRUGS AND KNOW
THAT IS ERADICATED WITH MORE
ROBUST METHODS?
WE UNDERSTAND MICROORGANISMS
WORKING TOGETHER TO GENERATE
THE CF ENVIRONMENT THAT CAUSES
THE GREATEST PROGRESSION.
WE WILL NEED TO UNDERSTAND
THAT.
OPTIMIZE CURRENT TREATMENTS AS
WELL AS DEVELOP NEW
ANTIMICROBIALS THAT WE WILL
IDENTIFY, THE LOW HANGING
FRUIT THAT HAVE AVAILABLE AS
WELL AS IN OTHER FORMS AND
IDENTIFY THAT BROAD SPECTRUM
OF CF FOR THE LANDSCAPE.
EVALUATE THE ANTIMICROBIAL USE
AND INFECTION.
WE KNOW THIS IS CURRENTLY
CHANGING BUT NOT GOING AWAY,
SO WHAT PATHOGENS ARE
PROBLEMATIC AND WHICH ARE
CAUSING PROGRESSION WILL
BECOME AN URGENT QUESTION TO
ADDRESS AND THEN FINALLY I
THINK AS WE HAVE SEEN, SOME
PATIENTS HAVE SPONTANEOUS
ERADICATION OF THEIR
DELETERIOUS PATHOGENS AND I
THINK THIS MIGHT SHOW HOW WE
ERADICATE LONG-TERM THOSE ON
HIGHLY EFFECTIVE MODULATOR
THERAPY.
NEXT SLIDE.
SO WE HAVE A TABLE OF THE
VARIOUS THINGS IN DEVELOPMENT,
OBVIOUSLY IN TRIALS WHICH THE
RESEARCH COMMUNITY IS PURSUING
BUT ALSO IDENTIFYING
APPROPRIATE PATIENT
POPULATION.
YOU CAN SEE BY THE CLASS
GROUPINGS ON THE RIGHT SIDE OF
THE SLIDE, THE ESTABLISHED
THERAPY BUT CASE STUDIES THAT
IT BECOMES TRANSFORMATIVE FOR
CERTAIN INDIVIDUALS.
SO WE REALLY TRY TO HELP BRING
CLARITY WITH RANDOMIZED
CONTROL STUDIES THAT ARE WELL
DESIGNED IN THIS AREA AND YOU
CAN SEE THERE ARE A NUMBER OF
STUDIES ONGOING WITH VARIOUS
FORMS OF PHAGE IN TRYING TO
ADDRESS THIS.
THERE ARE ALSO BROAD SPECTRUM
ANTIMICROBIALS THAT WORK WITH
THE E MECHANISM ALONG WITH
DRUGS THAT HAVE NO MECHANISM.
NEXT SLIDE.
THE ANTI-INEFFECTIVE PORTFOLIO
IS ROBUST SO AGAIN A SECOND
SLIDE SHOWING THE VARIOUS
PATHWAYS BEING ATTACKED IN
TRYING TO ADDRESS THIS.
BIODISRUPTORS IS ONE EXAMPLE
WHERE WE HAVE THE NEW SCIENCE
EMERGING BUT THERE IS ALSO THE
MR SA OR ANTI-FUNGAL THERAPY
AND A NOVEL TECHNIQUE WITH
ANTIMICROBIAL TECHNOLOGY THAT
CAN MAKE THESE DRUGS AVAILABLE
SO THAT WILL BE AN AREA OF
INTEREST ESPECIALLY FOR
PATHOGENS THAT HAVE BEEN
DIFFICULT TO TREAT AND
ERADICATE IT.
NEXT SLIDE.
ADDITIONAL SYMPTOMATIC
THERAPIES ARE IMPORTANT BUT
THIS IS IN THE LANDSCAPE WITH
PATIENTS AT THE LEVEL OF
EXPECTORATION RESOLVED IN SOME
BUT NOT OTHERS.
THE MUCOLYTICS WITH DISRUPTO
RS AND REDUCERS.
THERE ARE ALSO HIDE TRAITORS
WITH THE CELL EXPRESSION
INCLUDING ENAC INHIBITION,
ALTERNATE CI CHANNEL ACT
VARIETIES, ANTI-INFLAMMATORY
AGENTS.
ONE THAT MIGHT BE PARTICULARLY
CHALLENGING TO DEVELOP FOR CF
BECAUSE OF THE LONG-TERM
THERAPY NEEDED AND I POINT OUT
THE NEED FOR SHORTER ENDPOINTS
WITH THIS BUT ALSO LONG-TERM
PRIORITIES FOR THOSE WITH CF.
OTHER PRIORITIES NEED TO BE
DEFINED.
A CLEAR PICTURE OF WHAT PEOPLE
ARE HIGHLY EFFECTIVE MODULATOR
THERAPY ARE EXPERIENCING,
DEFINING THE POPULATION WITH
PROGRESSIVE DISEASE OR UNMET
NEEDS, INFORMED BY THE
CATEGORY OR WHO RESPOND FOR
UNKNOWN REASONS AND THEN THE
RESULTS OF OUR ONGOING
CLINICAL TRIALS THAT ARE
STUDYING PATIENTS ON HIGHLY
EFFECTIVE MODULATOR THERAPY AS
THE FIELD HAS CHANGED
THROUGHOUT THE DESIGNS OF THE
STUDY.
NEXT SLIDE.
IF YOU LOOK AT THE LANDSCAPE
OF MUCOCILIARY AND
ANTI-INFLAMMATORY PROGRAMS,
YOU CAN SEE THERE ARE ALSO
QUITE A FEW AND SPAN VARIOUS
CLASSES OF ANTI-INFLAMMATORY
AGENTS AND AT THE BOTTOM
INCLUDES PATHWAYS THAT ARE
TRIED AND TRUE BUT MAYBE SOME
THAT HAVE BEEN RECENTLY
IDENTIFIED AND SHOWN TO BE
EFFECTIVE.
THERE IS ALSO MUCOUS HYDRATION
AGENTS, MUCOLYTIC CAN AND SOME
WE HEARD ABOUT EARLIER TO
IMPROVE ELASTICITY.
NEXT SLIDE.
NOW OUR TRANSITION TO THE PATH
TO A CURE TREATMENT.
OBVIOUSLY IT INVOLVES MANY
DIFFERENT WAYS TO GET THERE
BUT WITH THE ULTIMATE MISSION
OF RESTORING CFPR FUNCTION FOR
ALL AND TO NORMAL LEVELS.
THIS IS A LARGE INVESTMENT FOR
THE FOUNDATION TO ACCELERATE
THIS BUT IT CAN'T BE DONE
WITHOUT THE PARTNERSHIP OF NIH
TO UNDERSTAND THE BASIC
BIOLOGY ON HOW TO EXECUTE
GENETIC THERAPY RESOURCES
ABOVE AND BEYOND.
AND THIS IS BUILT ON A PREMISE
WE MAY EVEN NEED TO ADDRESS
OTHER GENETIC DISEASES WITH
THE PROMISE IT COULD
ACCELERATE DRUG THERAPY FOR
PEOPLE WITH CF IN PARTICULAR
CASES.
NEXT SLIDE.
WE CAN CONSIDER THE MAJOR
STRAT WE DO AND IF YOU WILL
ADVANCE, YOU CAN SEE THE PATH
TO A CURE THERAPIES INVOLVES A
LOOK AT DNA THAT COULD BE
DIFFERED BY GENE DELIVERY OR
EDITING.
OUR RNA MODALITY AS WELL AS
THE WAY TO ADDRESS RNA
REPLACEMENT OR INHIBITION OF
PATHWAYS IRRELEVANT TO
CORRECTION.
AND WE HAVE SEEN QUITE A FEW
OF THESE IN THE LANDSCAPE AND
OBVIOUSLY EFFECTIVE MODULATORS
HAVE BECOME A VERY IMPORTANT
CORNERSTONE WITH CF
MANIFESTATIONS AND THERAPY.
NEXT SLIDE.
YOU CAN SEE THE AMOUNT OF
RESEARCH IN THE PRECLINICAL
STAGE AND INVESTMENT IS REALLY
UNPRECEDENTED.
IT INCLUDES MULTIPLE PROGRAMS
IN EACH OF THE CATEGORIES ON
THE SLIDE INCLUDING CRISPR AND
TRANSMITTING NOT ONLY SHORT
TERM BUT LONG-TERM GENETIC
MODULATION TYPE THERAPY BEING
A MAJOR PRIORITY AND THUS A
HEAVY AREA OF INFLUENCE.
THIS INCLUDES BOTH VIRALS,
NONVIRALS AND OTHER PROGRAMS
TO ACCOMPLISH THIS.
GENE EDITING INCLUDING TAKING
ADVANTAGE OF THE REMARKABLE
CRISPR TECHNOLOGY AS WELL AS
NON-CRISPR TECHNOLOGY THAT IS
RISING VERY RAPIDLY FOR THOSE
CURRENTLY UNTREATED.
OTHER MODELS AND TOOL
PROGRAMS, ACCELERATE RESEARCH
AS WELL AS UNIQUE PARTNERSHIPS
WITH VENTURE FIRMS TO TRY TO
GENERATE MULTIINSTITUTIONAL
AND PA*RPLA COLLABORATIVES TO
ADDRESS THE PROBLEMS IN A
UNIQUE WAY -- PHARMA
COLLABORATIVES.
NEXT SLIDE.
A LOOK AT THE NEW MODULATOR
PROGRAMS REPRESENTED IN THIS
SLIDE, PHASE 3 OF THE PROGRAM
IS IN PROGRESS AND IT MAY BE
THAT DIFFERENT COMBINATIONS
WILL BE AVAILABLE TO TREAT
VERY DIFFICULT AND CORRECT
MUTATIONS WHICH THEORETICALLY
HAS BEEN POSSIBLE BUT
DIFFICULT TO ACHIEVE IN THE
THERAPEUTIC RANGE FOR SOME
PATIENTS, THE PRE-K EXAMPLE IS
FEASIBLE WHERE IT COULD
ADDRESS ONE OR MORE MOLECULES.
NEXT SLIDE.
WE CAN ALSO CONSIDER A
READTHROUGH, YOU CAN SEE THIS
IS ALSO GROWING FROM THE
CLINIC INCLUDING ONE THAT HAS
SHOWN A SMALL CHANGE THAT AT
LEAST ESTABLISHES THE PROOF OF
CONCEPT THAT THESE PATIENTS
MAY ALSO BE AMENABLE TO THESE
SORTS OF MODULATION TECHNIQUES
AND THERE ARE OTHER
PRECLINICAL PROGRAMS MOVING
TOWARDS CLINICAL CANDIDATES.
AND THEN THE NUCLEOTIDE
THERAPY REMAINS AN APPROACH
FOR SOME PATIENTS, HIKE THE
3849 PATIENTS LISTED WHERE
THEY ARE ABLE TO TAKE CERTAIN
CF MODULATORS BUT THE
POTENTIAL THERAPY HAS NOT YET
BEEN ACHIEVED FOR NORMAL
FUNCTION.
NEXT SLIDE.
THIS IS A SCHEMATIC YOU HAVE
SEEN BEFORE THAT LOOKS AT HOW
WE MIGHT REPAIR OR REPLACE THE
CF DEFECTIVE CFTR GENE CAN
DNA-TARGETED THEIRS AND IN
ASSOCIATION WITH THAT, LOOKING
AT THE VEHICLE, THE DURATION
AND AS WELL HOW WE MIGHT
DELIVER THAT IN THE CF LUNG AS
WELL AS TECHNOLOGIES THAT ARE
TARGETING THE CORRECT ZONE,
LOOKING AT THOSE BEYOND OR
CERTAIN CELL TYPES OR THOSE WE
HAVE LEARNED ABOUT THE LAST
FEW YEARS ABOUT WHICH CELL
TYPES ARE PARTICULARLY
IMPORTANT FOR CFTR EXPRESSIONS
TO BE PRESENT IN WHICH NORMAL
PHYSIOLOGY WILL BE NEEDED FOR
THAT TO OCCUR, AS WELL AS
ULTIMATELY TARGETING CFR
THROUGHOUT THE BODY AND HAVING
THE SORTS OF TARGETING VECTOR
THAT WOULD ALLOW THAT TO OCCUR
AND ULTIMATELY PROVIDE A CURE.
NEXT SLIDE.
OTHER-- SOME NOTABLE RESEARCH
PRIORITIES OF THE GENETIC
THERAPY ERA THAT WE ARE HIGHLY
ENCOURAGING AND LOOK IN PART
FOR NIH TO ACCELERATE IS
UNDERSTANDING THE EPITHELIAL
BIOLOGY, CELL TYPES AND
TARGETING TECHNOLOGIES
NECESSARY TO ACHIEVE.
SO THRESHOLDS REQUIRED FOR
EFFICACY, WE HAVE LEARNED
THIS, ON THIS TOPIC AND
OTHERS, THE CF MODULATION AND
NOW WE CAN LOOK AT THE
HEITEROGENEITY IN CELL TYPES
AND RESTORING FUNCTIONAL
BIOLOGY.
VECTOR TECHNOLOGIES TO
ACCOMPLISH EFFICIENT DELIVERY,
A STEP FOR MANY.
ADVANCES IN GENETIC CAR GO,
THAT IS ACCELERATING QUICKLY,
INCLUDING ANIMAL MODELS TO
FACILITATE AND PREDICT
CLINICAL TRANSLATION.
LOOKING AT OUTCOME MEASURES
FOR GENETIC-BASED THERAPIES,
CLINIC TALL TRIAL DESIGNS, I
HAVE ALREADY SPOKEN TO THAT
AND THEN FINALLY DEFINING
RISKS OF TRANSIENT AND
TERMMENT THERAPIES GIVEN THE
POTENTIAL FOR RISK.
NEXT SLIDE.
SO THIS IS THE LANDSCAPE OF
GENETIC THERAPIES.
WE OBVIOUSLY HAVE LEARNINGS
FROM THE MODULATOR PROGRAM AS
WELL AS A NUMBER OF GENETIC
THERAPY APPROACHES THAT ARE
REACHING THE CLINIC AND
STARTING TO LEARN NOW AS WELL
AS THE RESEARCH EXPERIENCE OF
A COMPOUND NOT EFFECTIVE BUT
WILL PROVIDE SOME EXPERIENCE
MOVING FORWARD.
NEXT SLIDE.
SO WE'RE WORKING TO PROVIDE
GUIDANCE FOR INDUSTRY, LOOKING
TO DEVELOP A NETWORK FOR
EDUCATION PRIORITIES AMONG THE
COMMUNITY, RESEARCH TEAMS AND
CARE TEAMS AND THEN WE WILL BE
SPENDING A LOT OF TIME
CONSIDERING HOW THE NOVEL
CLINICAL TRIAL DESIGNS AND END
OPINIONS WILL BE EXECUTED AND
THAT WILL BE A CONSIDERABLE
AMOUNT GOING FORWARD.
SO YOU CAN SEE HERE IN
PARTNERSHIP WITH NIH ON
FUNDAMENTAL RESEARCH QUESTIONS
WHICH WILL ENABLE EVALUATION,
TESTING AND DEVELOPMENT OF
GENETIC BASED THERAPIES IS
CRUCIAL.
CRITICAL ACADEMIC INNOVATION
IS NEEDED IN PARTNERSHIP WITH
THE NIH AND WE LOOK FORWARD TO
THAT ROLE.
LABORATORIES OF CFF AND
ACADEMIC PARTNERS POISED TO
MAKE REAL PROGRESS IN
COLLABORATIVE RESEARCH AREAS
AND SUCCESS.
THANKS VERY MUCH AND I AM
HAPPY TO PASS IT ALONG TO OUR
NEXT SPEAKER.
>> SO WE ARE DISCUSSING THE
RESEARCH FOR CYSTIC FIBROSIS
AND DRUGS THAT CAN TURN THE
DEADLY DISEASE INTO A
MANAGEABLE CONDITION AND WE
HAVE THE TIMELINE HERE
STARTING WITH APPROVAL IN 1984
AND ADVANCING FORWARD IN 2012
WITH THE FIRST APPROVAL OF THE
HIGHLY EFFECTIVE MODULATOR
THERAPY AND THEN LEADING US TO
THE PRESENT DAY.
NEXT SLIDE.
SO THE GOAL TODAY IS TO
PRESENT KEY EVIDENCE FROM
PHASE 3 AND OBSERVATIONAL
STUDIES WITH FUNCTIONAL AND
MECHANISTIC OUTCOMES AND AS
YOU CAN SEE ON THE SIDE, THE
FUNCTION WE HAVE, ASSESSING
INFECTION AND INFLAMMATION AND
THE NUTRITIONAL PART OF THAT.
THIS IS REALLY A SUMMARY OF
INFORMATION COMING FROM PHASE
3 RANDOMIZED CONTROL TRIALS,
THE REGISTRY DATA TO REFLECT
WHERE WE ARE NOW BUT REALLY
THIS IS LOOKING FORWARD AT
OPPORTUNITIES TO UNDERSTAND
MORE IN GAPS IN OUR HIGHLY
EFFECTIVE MODULATOR THERAPY
AND WHERE WE ARE GOING WITH
INFECTION, INFLAMMATION, THE
LIVER EFFECTS, LOOKING AT
TOLERANCE AND ADHERENCE AND
ALL OF THESE WILL IN THE
FUTURE CONVEY WHERE WE ARE
GOING.
NEXT SLIDE.
SO TO START THIS SUMMARY, WE
HAVE TO LOOK BACK TO THE FIRST
BREATHTAKING DATA THAT WERE
PUBLISHED IN 2011 INCLUDING
IVACAFTOR, THE FIRST HIGHLY
EFFECTIVE MODULATOR THERAPY
AND IT IS HARD NOT TO NOTICE
IN EVERY ONE OF THESE PANELS
THE KEY OBSERVATIONS OF THE
IMPACT OF THERARY ON CF.
YOU CAN SEE IT STARTS WITH
JUST 10 PERCENT IMPROVEMENT
RELATIVE TO THE PLACEBO GROUP
AND THEN CONTINUING ON THROUGH
THE 48 PERIOD TIME COURSE AS
WELL AS PANEL B, REFLECTION OF
THE EFFECT, THOSE TREATED WITH
IVACAFTOR AND ANTIBIOTICS.
YOU CAN SEE IN C OVER TIME,
MARKED IMPROVEMENT AND IN
PANEL D, THE FIRST
IMPROVEMENTS WE HAD SEEN OF
THIS NATURE IN BODY MASS INDEX
AND FRANKLY A CHANGE IN WEIGHT
BUT WHEN WE STARTED TO LOOK AT
THE MECHANISM OF THIS CLINICAL
BENEFIT, YOU CAN SEE IN PANELS
A AND B ON THE RIGHT THAT
FLUORIDE WAS DROPPED IN THIS
MARKED INDICATOR.
SO YOU CAN SEE IN PANEL A THE
FLUORIDE AND THEN IN PANEL B,
THE REDUCTION AND THEN IN D,
CONSIDERED AS A DIAGNOSIS WHEN
TAKEN TOGETHER WITH CLINICAL
SYMPTOMS AT THE TIME.
SO WE FOLLOWED THE PATIENT FOR
FIVE YEARS IN U.S. AND UK
REGISTRY DATA AND CONTINUED TO
SEE IMPROVEMENT WITH THERAPY.
A AND B ON THE LEFT ARE THE
PROPORTION OF PATIENTS TREATED
WITH IVACAFTOR WERE LOWER THAN
THE PHENOTYPE IN THE U.S. AND
U.K. OVER FIVE YEARS.
AND THEN YOU CAN SEE IT WAS
DECREASED AFTER ONE YEAR AND
REMAINS SLIGHTLY DECREASED
OVER TIME.
SO SOME OF THE DATA WE WILL
GET INTO FURTHER IN THIS
DISCUSSION WILL SHOW IN MORE
GRANULAR DETAIL AND FINALLY IN
THE RIGHT PANEL WHAT WE CAN
SEE AS WE LEARN ABOUT IN THIS
ERA FOR THE MAJORITY IF NOT
ALL OF THE PANELS.
SO YOU CAN SEE THAT THERE HAS
BEEN AN INCREASE OVER THE
INITIAL PERIOD BUT AS FOLLOWED
OVER THE FIVE-YEAR PERIOD, YOU
CAN SEE THERE IS SOME SLIDE IN
FV1 AND THAT WAS ALSO SEEN IN
THE UNITED KINGDOM IN THE
INITIAL YEAR BUT FOLLOWING
THAT OVER THE COURSE OF TIME.
SO TO TRY TO UNDERSTAND WHAT
IS LEADING TO THAT, WE WILL
HAVE TO LOOK FURTHER AT THIS
WITH --
[INDISCERNIBLE]
SO IF WE GO TO THE NEXT SLIDE.
THE LONG-TERM EFFECTS OF
IVACAFTOR WERE HOOKED IN A
LONG-TERM OBSERVATIONAL STUDY
AND OVER THE COURSE OF SIX
MONTHS, IT WAS EVIDENT THE
MEASURES CHANGE IN PMI, BLOOD
CLOTTING MEASURES WERE ALL
PRESERVED ALTHOUGH THERE WAS
SOME DECREASE IN THE
RESPIRATORY IN PANEL B.
WHAT WE HAVE SEEN IN A SET OF
31 PATIENTS INDICATING
INFLAMMATORY MEASURES AS SHOWN
IN THESE BIOMARKERS IN EACH OF
THESE PANELS AS WELL AS OTHER
ORGANISMS WERE NOT HIGHLY
EFFECTIVE AND THIS MAY SHOW US
THE HIGHLY EFFECTIVE MODULATOR
THERAPY OVER TIME.
NEXT SLIDE.
SO IT DOES APPEAR THAT I IT IS
HERE TO STAY.
IN THE WHITE PANEL ON THE LEFT
OF EACH OF THESE, THE 24 WEEK
DATA FOLLOWED BY THE SHADED
DATA IN THE ENSUING 24 WEEKS
OF THE STUDY AND YOU CAN SEE
IN THE BOTTOM RIGHT THERE IS A
BIT OF A POSTER BY Dr.
COREY DAINES AND WHILE THAT IS
NOT AVAILABLE IN THE DATA, I
CAN HYPOTHESIZE ON THAT DATA.
AS YOU CAN SEE HERE IN BOTH OF
THESE PANELS AT THE TOP, THESE
APPEAR TO BE STABLE AT 24
WEEKS AND THEN AS SHOWN IN THE
POSTER FROM Dr. DAINES,
THERE DOES NOT SEEM TO BE A
SIGNIFICANT CHANGE IN THE 24
WEEK PATH.
SIMILARLY YOU CAN SEE THE
REDUCTION OF THE FLUORIDE AND
FOLLOWED BY ANOTHER 24-WEEK
PERIOD AND IT DOES PERSIST
SHOWN IN THE POSTER IN THE
FALL OF 2021.
NEXT SLIDE.
SO ONE OF THE QUESTIONS WE
PHASE NOW IS, IS IT POSSIBLE
TO BUILD ON BETTER?
AND THIS IS A PHASE 3 STUDY
WITH 132 PATIENTS GLOBALLY
ALREADY TAKING A CF MODULATOR
AND FEIGNING FUNCTION SO IT
WAS A COMBINATION.
AND IN THIS STUDY, WE ADDED
THE MODULATOR AND SAW A .
5 PERCENT EFFECT.
AND THE PROPORTION ON THE LEFT
PANEL OF PATIENTS THAT HAD
SWEAT CHLORIDE DECREASES ARE
SHOWN IN THIS BLUE COLUMN,
83.3 PERCENT OVERALL FOR
PATIENTS TREATED ON THIS
THERAPY.
AND WHAT IS EVEN PERHAPS
FURTHER REMARKABLE WHEN WE
CONSIDER THE RIGHTHAND PANEL
FOR THE PROPORTION OF PATIENTS
WITH THE SWEAT CHLORIDE LEVEL
THAT ENDED WITH LESS THAN 30ML
PER LITER.
WHAT WE SEE IS THAT 50 PERCENT
OF THE STUDIED POPULATION
OVERALL ACHIEVED THESE LOW
LEVELS OF SWEAT CHLORIDE AND
AGAIN 65.1 PERCENT EFFECTIVE
FOR THEIR GENOTYPES AND
MODULATOR THERAPY.
SO NEXT SLIDE.
LOOKING AT THESE SLIDES, WHAT
DOES THE DATA MEAN?
WHEN YOU LOOK AT THE FIVE-YEAR
SURVIVAL IN CF PATIENTS,
CLEARLY WE CAN SEE THERE IS AN
INCREASE OVERALL.
IN 1989 ALL WAIT TO THE LEFT
OF THIS Y AXIS WHEN CF WAS
FIRST DISCOVERED, THE MEDIAN
AGE WAS ALMOST 30 YEARS OLD.
IF YOU LOOK TO THE FAR RIGHT
IN THE 2018-19 ANALYSIS, THIS
IS REACHING 40 YEARS OLD AND
THIS IS FOR THE FDA APPROVAL
OF IVACAFTOR.
SO YOU CAN SEE THE 20-YEAR
INCREASE IN SURVIVAL AGE WHICH
IS JUST STARTING TO ENCOMPASS
THE EFFECTS OF ETI.
AND ALSO ON THE RIGHT YOU CAN
SEE THE SIMILAR DECREASE
BETWEEN 2019 AND 2020 WITH THE
A MORTALITY RATE.
WHAT IS CHALLENGING TO
DECIPHER IS WHAT ARE THE
CONFOUNDING FACTORS AS THE
COVID-19 PARTLY CLOUDY SPREAD
WORLDWIDE AND THE EFFECTS OF
SOCIAL DISTANCING AND
QUARANTINE WERE DIFFICULT TO
PARSE AS YOU LOOK AT MORTALITY
OVER TIME AND ALSO OVERLAP THE
START OF WIDELY ACCEPTED ETI
THERAPY.
NEXT SLIDE
>> TWO-MINUTE WARNING.
>> THANK YOU SO THIS SLIDE
MAY PROVIDE US SOME FIRST
CLUES AS WE LOOK AT THE
COMPARATOR OF PULMONARY
DISEASE, WE SEE A SHARP
DROPOFF IN 2020 AND WHILE WE
SEE COPD ALSO INCREASED IN
2020, BUT ALSO DURING A TIME
OF SOCIAL DISTANCING AND
QUARANTINE.
NEXT SLIDE.
SO 478 INDIVIDUALS IN A
SIX-MONTH PLANNED ANALYSIS AND
OBSERVATIONAL STUDY OF
PATIENTS WHO WERE PRIOR TO
MODULATOR THERAPY OR WERE ON
MODULATOR THERA PY AND WHAT WE
SEE IS AT THREE MONTHS AND SIX
MONTHS, RAISES THAT TO
OBSERVATIONAL STUDIES SO WE
ARE STARTING TO SEE THAT THERE
IS SOME RISE THAT IS RELATED
TO TREATMENT AND CARE AND THIS
STUDY IS ONGOING.
AND IF YOU ADVANCE THE SLIDE,
YOU CAN SEE RELATIVE
COMPARISONS TO THESE DATA WITH
G551D AND IVACASTOR.
NEXT SLIDE.
SWEAT CHLORIDE VALUES HAS BEEN
ANALYZED INDEPENDENTLY, THESE
ARE UNPUBLISHED DATA OF 26
INDIVIDUALS AND WHAT WE SEE
INDIVIDUALLY IS THESE
INDIVIDUALS ARE TRACKING THOSE
WITH THE DECREASE IN SWEAT
CHLORIDE AFTER THER APIES.
SO QUICKLY, NEXT SLIDE, I
WOULD SAY IF YOU LOOK AT THE
COMBINATION OF THESE AND THE
THE IVACAFTOR OR TRIKAFTA TONE
AS A COMBINED THERAPY SHOWING
HIGHLY MODULATED EFFECTS AT
THE SIX MONTH LEVEL AND WILL
CLINICALLY AT THE OUTCOME OF
TREATING THE UNDERLYING CF.
NEXT SLIDE.
BUT APPARENTLY ALL THAT
GLITTERS IS NOT GOLD.
IN STUDYING THIS DATA, WE KNOW
WE ARE LOOKING AT A FUTURE OF
BMI FOR ADULTS AND WHERE THIS
IS GOING AND SEEING THIS LIKE
NEVER BEFORE.
NEXT SLIDE.
AND THERE ARE A NUMBER OF
INTOLERANT CONSIDERATIONS
CONSIDERED FOR PEOPLE WHO
CANNOT TAKE THE MODULATOR
THERAPY AND WHERE THAT LEAVES
THEM TODAY.
NEXT SLIDE.
SO I WILL TRANSITION OVER TO
THE NEXT SPEAKER ON THE MANY
STUDIES CURRENTLY REFLECTED
HERE WITH MORE THAN 7800
PARTICIPANT TO BEGIN
ADDRESSING THIS AND IT HAS
BEEN A LOW PRESSURE SURE TO BE
ABLE TO PRESENT.
THANK YOU.
>> THANK YOU SO MUCH.
GOOD MORNING EVERYONE, WE ARE
THROWING A LOT OF INFORMATION
AT YOU REALLY FAST SO I JUST
WANTED TO TAKE A BREATH THAT
WE'RE ALL SO FORTUNATE TO TAKE
BEFORE I DIVE INTO MY STORY.
[ EXHALING HEAVILY ]
>> OKAY, MY NAME IS MELANIE
LAWRENCE.
I AM AN ADULT LIVING WITH CF.
I AM 41, JUST TURNED 42,
SORRY, HAVEN'T CAUGHT UP YET,
LIVING WITH CF AND I LIVE WITH
MY 11-YEAR-OLD SON MILES WHICH
IS AMAZING.
I HAVE BEEN WORKING WITH THE
CF FOUNDATION AT BOSTON
HOSPITAL FOR SEVERAL YEARS
NOW, QUALITY IMPROVEMENT
WORKSHOPS AND RESEARCH
OPPORTUNITIES AS WELL AS SIT
OINK ON THE SUCCESSFUL
THERAPIES RESEARCH CONSORTIUM
STEERING COMMITTEE.
I AM PASSIONATE ABOUT
COPRODUCTION CLINICAL
STRATEGIES AND HUMANIZING CF
CARE.
I HAVE PARTICIPATED IN
CLINICAL RESEARCH FOR DECADES
AND WITNESSED THE AMAZING
PROGRESS BEING MADE FIRSTHAND.
IT HAS BEEN BOTH AN HONOR AND
A PRIVILEGE TO CONTRIBUTE TO
THAT RESEARCH AND ALSO TO
BENEFIT.
I HAVE PERSONALLY BENEFITTED
AND I AM CURRENTLY
PARTICIPATING IN A NEW
CLINICAL TRIAL THAT GIVES ME
GREAT HOPE FOR WHERE WE ARE
GOING AND FOR THAT, I AM
DEEPLY GRATEFUL TO THE
ATTENTION BEING PAID TO OUR
COMMUNITY TRULY.
THANK YOU FOR PUTTING THIS
WORKSHOP TOGETHER AND SHEDDING
LIGHT ON THE EVOLVING NEEDS OF
OUR WORLD.
I UNDERSTAND THINGS ARE
CHANGING AT SUCH AN
ACCELERATED RATE THAT WE ARE
ALL LEARNING TOGETHER AND
TRYING TO KEEP UP.
THERE IS NO QUESTION THAT
MODULATORS HAVE CHANGED THE
LANDSCAPE AND THAT THE
MODELING NEEDS TO CHANGE WITH
IT.
MY MODULATOR EXPERIENCE HAS
BEEN OVERALL VERY POSITIVE BUT
IT HAS NOT BEEN THE MIRACLE
DRUG FOR ME THAT IT HAS BEEN
FOR MOST.
I HAD SOME --
[INDISCERNIBLE]
-- WHEN I STARTED SEVERAL
YEARS AGO AND TRIKAFTA HAS
STABILIZED MY CITIES AND NO
DOUBT GIVEN ME BETTER QUALITY
OF LIFE.
MY CFPS HAVE BECOME STEADY, MY
BREEZING IS BETTER AND ARE MY
SINUSES ARE MUCH HEALTHIER.
I DON'T WANT TO MINIMIZE THESE
BENEFITS BECAUSE THESE ARE
HUGE AND I AM GREATFUL FOR
THEM EACH AND EVERY DAY.
TRIKAFTA HAS GIVEN ME THE
ABILITY TO INDEPENDENTLY
IMPROVE MY HEALTH AND I AM
ABLE TO DEVOTE MORE TIME TO
EXERCISE AND MY MENTAL AND
EMOTIONAL WELL-BEING AND TO
CONTRIBUTE TO THINGS LIKE
MAKING ME FEEL LIKE I HAVE A
PURPOSE AND LIVING A FULL
LIFE.
I CAN SPEND LESS TIME FEELING
AWFUL OR EXPERIENCING SIDE
EFFECTS OF DRUGS AND SPEND
MORE TIME WITH OTHERS IN THE
HUMAN CONNECTION.
THAT BEING SAID, WE STILL HAVE
OUR WORK CUT OUT FOR US AND
THERE ARE MANY AREAS THAT WE
CAN IMPROVE UPON.
WHILE TRIKAFTA HAS HELPED TO
STABILIZE ME, IT DID NOT
DECREASE MY EPISODES AND HAS
NOT HELPED WHAT SEEMS TO BE
CAUSING MY CHRONIC EDEMA, HAS
NOT CHANGED MY CULTURAL
BACTERIA AND HAS NOT --
[INDISCERNIBLE]
I STILL EXPERIENCE MORE THAN I
LIKE.
I ALSO EXPERIENCE THE SIDE
EFFECTS THAT HAS AFFECTED MY
FOOD INTAKE AND QUALITY OF
LIFE.
WHILE I CONSIDER MYSELF
SUCCESSFUL --
[INDISCERNIBLE]
I RECENTLY PARTICIPATED IN A
WORKING GROUP ON THE
EXPERIENCE OF POST MODULATOR
ERA AND VERY MUCH LOOKING
FORWARD TO THE FINDINGS.
I THINK THIS COULD BE THE
FUTURE FOR US WITH FUTURE
RESEARCH IN EF.
ONE SENTIMENTS THAT HAS BEEN
ECHOED FOR A WHILE NOW IS HOW
ADULTS WITH MODERATE TO
ADVANCED DISEASE ARE STARTING
TO SEE --
[INDISCERNIBLE]
-- AND I AM GREATFUL TO SHARE
THE CHANGE WITH MODULATORS SO
MUCH, BUT OUR GENERATION IS
BEING DISREGARDED.
MANY HAVE SAID AND I AGREE
THAT WE NEED NEW ANTIBIOTICS
AND NEW THERAPY TO TREAT WHAT
HAS ALREADY BEEN DONE.
I AM RESISTANT TO EVERY
ANTIBIOTIC FOR MY BACTERIA AND
THE EFFECTS THAT ARE WORSE
PREVENT MY WANTING TO USE
THEM.
MANY STRUGGLE WITH RFD.
YES, IT IS AN ABSOLUTELY
AMAZING GIFT WE ARE LIVING IN
OUR LIVES BUT IT IS FAR FROM A
CURE.
YOU WILL HEAR MEANINGFUL
STORIES FROM OUR COMMUNITY,
ESPECIALLY THOSE NOT ELIGIBLE
FOR MODULATORS.
I HAVE NO DOUBT THIS WORKSHOP
WILL BE IMPACTFUL.
AS YOU SPOKE IN THE
INFORMATION YOU SHARED, I DO
CHALLENGE YOU TO DO THIS WORK
WITH A DIFFERENT LENS.
I ASK YOU NOT TO JUST LOOK AT
WHERE RESEARCH CAN GO BUT HOW
WE CAN MAKE RESEARCH BETTER,
MORE EFFECTIVE AND MORE
INCLUSIVE.
I IMPLORE YOU TO BUILD A
FRAMEWORK OF COMMUNITY AND
COPRODUCTION WITH YOUR WORK.
I RECENTLY HAD THE HONOR OF
SPEAKING AT A RESEARCH
CONFERENCE AND HIGHLIGHTING
THE DISCONNECT BETWEEN THE
ALGORITHM OF ADVICE AND HOW
LITTLE EFFECT TRICKLES DOWN TO
THE PATIENT EXPERIENCE.
RESEARCH NEEDS TO BE
SYMBIOTIC, HOWEVER YOU WANT TO
SAY IT.
YOU NEED US AND WE NEED YOU
AND PROGRESS HAPPENS WHEN WE
WORK TOGETHER.
SO MUCH OF OUR COMMUNITY
FEELSY HUMANIZED BY THEIR
EXPERIENCES, LEAVING AN OPEN
DOOR TO GROW AS A FIELD.
AS RESEARCHERS, PLEASE REMAIN
COGNIZANT OF HOW MUCH PATIENTS
ARE PUTTING ON THE LINE TO GET
THE DATA YOU NEED, TO REMEMBER
WE ARE ALL HUMAN BEINGS WITH
FULL LIVES WHO DESPERATELY
WANT TO WORK TOWARD THE SAME
GOALS YOU DO.
SHARING OUR ENVIRONMENT WITH
COMPASSION AND UNDERSTANDING,
IT IS SAID WE WILL BRING MORE
PARTICIPANTS INTO THE FOLD AND
WORK TOGETHER MORE
EFFICIENTLY.
IT IS NOT ONLY THE QUESTION OF
WHAT WE CAN ACCOMPLISH BUT HOW
WE WANT TO ACCOMPLISH.
I HOPE YOU CAN CARRY THIS
INCENTIVE WITH YOU DURING THIS
WORKSHOP AND WORK TO IMPLEMENT
MORE HUMANITY INTO YOUR
PRACTICES.
I THANK YOU SO MUCH FOR YOUR
TIME AND OPPORTUNITY TO SPEAK
WITH YOU TODAY.
WE NOW WILL WELCOME ANY
QUESTIONS YOU MAY HAVE AND I
PROMISE NO QUESTION IS
OFFLIMITS.
>> THANK YOU SO MUCH MELANIE
FOR THAT WONDERFUL SUMMARY AND
THANKS TO ALL OF THE SPEAKERS
PROVIDING INFORMATION, REALLY
POWERFUL WORK TO REMEMBER AS
RESEARCHERS AND ALSO --
[INDISCERNIBLE]
[ AUDIO DROPPING ]
I DO SEE WE HAVE A FEW
QUESTIONS THAT HAVE STARTED TO
COME IN AND ONE I CAN START
WITH, I THINK THERE WAS A
QUESTION EARLY ON, COULDN'T
FIND EXACTLY WHERE IT WAS
BECAUSE MARRAH PROVIDED SO
MANY WONDERFUL LINKS TO
EVERYBODY ON RESEARCH BUT IT
WAS ON THE SERIOUSNESS OF
SYMPTOMATIC THERAPIES WITH
HIGHLY EFFECTIVE MODULATORS
AND I POINTED TO THE FACT THAT
ALL THESE DRUGS WERE DEVELOPED
WERE DEVELOPED FOR MODULATORS
SO THERE ARE ADDED BENEFITS ON
TOP OF THAT SO I THINK THAT IS
KIND OF THE CONTEXT.
I THINK THE QUESTION I AM
GOING TO PROBABLY POSE IS
BETTER UNDERSTANDING SOME OF
THE RELATIONSHIPS BETWEEN
SWEAT CHLORIDE AND LONGER TERM
CLINICAL OUTCOMES, Dr.
DEEPIKA, DO YOU KNOW WHAT DATA
HAS BEEN ASPIRED IN THOSE
TOPIC AREAS?
>> I WAS ON MUTE.
YES, I HAD HOPED TO COVER
THAT.
ONE OF THE THINGS I DID AT
CHILDREN'S MERCY HOSPITAL, AND
THERE WERE MANY SO I ENCOURAGE
PEOPLE TO LOOK AT THE
MANUSCRIPT BECAUSE THERE ARE A
NUMBER OF STUDIES IN THAT DATA
BUT THE SWEAT CHLORIDE
MODULATION AT SIX MONTHS, IT
WILL BE VERY INTERESTING TO
SEE IF THAT CORRELATION
PERSISTS.
WE KNOW THESE ARE VERY COMPLEX
VARIABLES, FP1 AND SWEAT
CHLORIDE.
SO I THINK WE STILL FACE
CHALLENGES WITHIN THE SUBJECT
AND STILL NEED TO LOOK AT
CORRELATION OF SWEAT CHLORIDES
WITH CLINICAL OUTCOMES
GENERALLY SPEAKING BUT WE CAN
CERTAINLY SEE IT AFFECTS THE
BROADER POPULATION LEVEL AND I
THINK WE'RE LEARNING MORE ON
THE SWEAT CHLORIDE LEVEL.
SOMETIMES THESE ARE LINKED
TOGETHER IN THESE STUDIES AND
SOMETIMES NOT --
[INDISCERNIBLE]
ZO SO I THINK WE'RE STILL
LOOKING AT THAT.
>> GREAT, THANK YOU SO MUCH.
NEXT QUESTION I THINK I WILL
BRING TO STEVE BUT MAYBE YOU
CAN WEIGH IN A LITTLE BIT, THE
QUESTION WHETHER WE HAVE THE
DYNAMICS OF MODULATORS AND
PHARMACO MODULATORS, IF THERE
IS A CLARIFICATION, PLEASE PUT
IT IN THE CHAT.
>> YEAH, I THINK IT IS AN AREA
WE STILL DON'T KNOW FULLY
ABOUT BECAUSE MONITORING THE
LEVELS IN THE TISSUES HAS BEEN
MORE CHALLENGING ALTHOUGH WE
CAN START TO SEE SOME EMERGING
TECHNOLOGIES TRYING TO DO
THAT.
CERTAINLY IN THE DRUG DOSE
PATH, THE TK RELATIONSHIP
ESPECIALLY WITH THESE
MULTIDRUG COMBINATIONS HAS
BEEN COMPLICATED AND
PARTICULARLY COMPLICATED
BECAUSE THEY INTERACT WITH ONE
ANOTHER AND LEAD TO THE
METABOLISM OF ONE ANOTHER.
BUT NONETHELESS, THE
PREPONDERANCE OF THE DATA HAS
SHOWN ONCE THE THRESHOLD IS
ACHIEVED FOR DRUG LEVELS, THAT
IS GENERALLY CORRELATED WITH
IMPROVEMENT IN SWEAT CHLORIDE.
SO WE KNOW THE MAJOR EFFECT
HAS BEEN GETTING ABOVE THE
THRESHOLD.
HAVING SAID THAT, THERE ARE
NOW EMERGING CASES FOR
RESPONSE, DRUG INTERACTION
CASES RECORDED THAT SHOW IN
SOME CASES, THE SUBOPTIMAL
RESPONSE MAY BE AT LOW LEVELS
DESPITE THE DOSING BEING
NORMAL.
WE CAN IMAGINE THAT HAPPENING
BECAUSE OF THE METABOLISM OF
THESE DRUGS AND THEN FINALLY,
WE CAN SEE IT HAPPEN IN THE
LIVER BUT THEN THERE IS SOME
EARLY METABOLISM CONSIDERING
THAT MAY BE DIFFERENT FROM
WHAT YOU PREDICT FROM THE
SERUM AND IT MAY BE THAT A
METABOLIZING ENZYME VARIANCE
IS PART OF THAT STORY EXISTING
IN THE ARRAY.
SO I THINK THERE IS MORE TO
LEARN.
I CERTAINLY LOOK FOR FUTURE
SCIENCE TO SEE IN A
NONRESPONSIVE OR LESS
RESPONSIVE POPULATION IF DRUG
LEVELS OVER THE HISTORY LEVEL
HAVE AN EFFECT ON THE ORGANS.
>> THANK YOU FOR THAT -- [
INDISCERNIBLE ]
[ AUDIO.
>> I AM SORRY, I DON'T THINK I
CAN ANSWER THAT BETTER THAN
STEVE BUT I WANT TO ADD ON
GOING FORWARD, THE QUESTION OF
BEING ABLE TO UNDERSTAND WHO
WILL BE A RESPONDER WILL BE
MORE IMPORTANT AS WE SEE
THERAPIES BROADEN ON THE
HORIZON.
SO IN ADDITION TO THE POINT
STEVE BROUGHT UP, I WOULD ADD
THAT UNDERSTANDING THE
GENOMICS IS GOING TO BE
CRITICAL AND WE HOPE TO HAVE A
BETTER PREDICTION OF TREATMENT
RESPONSE OR OPTIMAL TREATMENT.
>> GREAT, VERY GOOD POINT,
THANK YOU FOR BRINGING THAT
UP.
ALSO MELANIE, I APPRECIATE
YOUR TALK AND HOPE YOU CAN SEE
HOW MANY APPRECIATED IT IN THE
CHAT.
COULD YOU SPEAK A LITTLE MORE
ABOUT HOW WE CAN BRING MORE
HUMANITY TO HOW WE CONDUCT OUR
RESEARCH --
>> WELL, YOU FROZE THERE AT
THE END BUT I SAW THE QUESTION
AND I AM HAPPY TO ANSWER.
THERE ARE WAYS TO BRING MORE
HUMANITY TO RESEARCH.
THE CF FOUNDATION HAS THIS
PROGRAM CALLED THE PEP
PROGRAM, THE PARTNERSHIP
ENHANCEMENT PROGRAM IN WHICH
TRAINING CLINICIANS AND
RESEARCHERS ON CONCRETE
METHODS TO COMMUNICATE FOR A
MORE EMPATHETIC PLACE AND TO
ENGAGE ON A DEEPER LEVEL WITH
PATIENTS.
THAT ASIDE, I DO THINK IT IS
REALLY SO SIMPLE, AND IF YOU
THINK ABOUT IT, IT IS LIKE A
MICROKOES MOST OF HUMAN
EXPERIENCE.
RESEARCH IS SO CONCISE AND YOU
HAVE SO MUCH TO GET DONE IN A
SHORT AMOUNT OF TIME AND WE
FEEL THAT.
SO MAYBE BEFORE YOU GO INTO
THE ROOM, STOP, TAKE A BREATH
AND THEN CONNECT WITH THE
PATIENT ON A HUMAN LEVEL
BEFORE YOU DRIVE IN TO ALL OF
THE RESEARCH QUESTIONS.
ACKNOWLEDGE THEIR SACRIFICE.
YOU KNOW, WE'RE PUTTING OUR
BODIES ON THE LINE TO GIVE YOU
DATA AND PROGRESS, JUST
ACKNOWLEDGE AND APPRECIATE
THAT BUT ALSO LIKE I CONNECTED
A LOT MORE WITH RESEARCHERS
AFTER I LEARNED WHAT THEY
LIKED ABOUT RESEARCH, WHAT
DROVE THEM TO DO IT, WAS IT A
REWARDING JOB OR A GRUELING
JOB SO THAT ALLOWED ME TO
CONNECT WITH THEM AS A HUMAN
BEING SO SHARE A LITTLE MORE
ABOUT YOURSELF AND CONNECT
WITH YOUR PATIENTS AS WELL.
>> THIS IS MARRAH.
I WILL GO AHEAD AND JUMP IN
BECAUSE I THINK WE HAVE LOST
JP BUT I HAVE BEEN COLLECTING
THE QUESTIONS.
MELANIE, WE HAVE ANOTHER
QUESTION FOR YOU THAT COMES
FROM Dr. ROSENTHAL, SHE
WANTED TO TACK ON TO TERRY'S
QUESTION WHICH IS DO YOU SEE
DECENTRALIZATION OF TRIALS
LIKE BEING ABLE TO COLLECT
ENDPOINTS AT HOME SUCH AS
SPIROMETRY AT HOME AS A WAY TO
IMPROVE CLINICAL TRIAL
EXPERIENCE.
>> IT IS INTERESTING BECAUSE
I THINK IT IS A WHETHER HE
ISING AND A CURSE.
IT CAN BRING MORE PATIENTS
INTO RESEARCH FROM THAT
STANDPOINT, TO GET A DIFFERENT
POOL OF PARTICIPANTS BUT I DO
THINK THERE IS SOMETHING THAT
IS LOST IN THE FACE TO PACE
EXPERIENCE.
I THINK THAT THERE'S A NUANCE,
BEING FACE-TO-FACE WITH
SOMEONE, THAT MORE WILL COME
UP AND IF YOU ARE JUST
COUNTING ON HOME DATA, LIKE
HOME SPIROMETRY THERE ARE MANY
NUANCES THAT ARE LOST AND
SYMPTOMS NOT SHARED OR
EXPERIENCES THAT MIGHT BE LEFT
OUT.
SO I THINK IT IS HELPFUL BUT
NOT THE FULL ANSWER EITHER.
>> THANK YOU, THAT IS A GREAT
PERSPECTIVE AND THE VALUE OF
MAKING THE PERSONAL CONNECTION
AS YOU SAID IN YOUR TALK IS
REALLY IMPORTANT AND YIELDS
ADDITIONAL INSIGHT.
SO I HAVE A QUESTION FOR Dr.
ROWE AND NOT SURE YOU CAN
ANSWER BUT IT POPPED UP IN THE
CHAT BUT HOW EFFECTIVE IS
EDD20 AS A HIDE TRAITOR?
>> FOR THOSE NOT FAMILIAR,
THIS IS A COMPOUND PRESENTED
AT THE CF MEETING FOR CLINICAL
DEVELOPMENT, A DRUG COULD BE
ON THE HORIZON, MEANING IT
ACTIVATES OF ALTERNATIVE
CHLORIDE CHANNEL AND WHAT HAS
BEEN SHOWN IS THAT IN VITRO,
IT IS A QUITE POTENT AND
EFFICACIOUS DRUG AND DOES SO
DIRECTLY IN THE CHANNEL AS
OPPOSED TO OTHER INDIRECT
CHANNELS.
IT HAS BEEN SHOWN TO AUGMENT
AIRWAY SURFACE LIQUID DEPTH
AND DO SO STRONGLY AND IT HAS
ALSO BEEN REPORTED TO KNOCK
THE MUCOUS SECRETION WHICH HAS
BEEN A POTENTIAL RISK ON THE
PATHWAYS --
[INDISCERNIBLE]
SO I THINK IN VITRO IT LOOKS
PROMISING.
WE KNOW THAT THE EMAM CHANNEL
AND SWEAT CHLORIDE ON THE
SURFACE ARE EFFECTIVE BUT WE
DON'T YET KNOW WHETHER THAT
WILL TRANSLATE TO MUCOUS
CLEARANCE.
IT IS EXPRESSED IN SIMILAR IPR
SO THAT IS A GOOD SIGN IT
SHOULD AND WE'LL KNOW MORE
WHEN IT REACHES THE CLINIC.
IT CERTAINLY CHECKS THE RIGHT
BOXES AS FAR AS THE PHYSIOLOGY
SEEN IN THE STUDIES.
>> SO LOOKS LIKE WE HAVE TWO
MINUTES LEFT.
I WILL POSE THIS LAST QUESTION
BEFORE WE MOVE TON FROM
SESSION 1 AND THIS IS FROM THE
CHAT.
CAN YOU TALK'HOW WE ARE SYSTEM
ATICALLY STARTING MODULATORS
EARLY IN LIFE AND HOW THIS CAN
BE ADDSES, THIS IS ALSO A
QUESTION FROM OTHER SESSIONS
BUT I THINK YOU GUYS CAN TALK
ABOUT IT NOW.
>> Dr. POLINENI, YOU WANT
TO START IT OR YOU WANT ME TO
TRY?
>> SURE, SO I NOTICED THIS
QUESTION FROM DENNIS IN THE
CHAT AS WELL AND I THINK THE
TWO APPEAR TOGETHER BECAUSE
WHEN WE'RE STARTING TO THINK
ABOUT VERY EARLY ON IN
THERAPY, WE LOOK AT ACTIVATION
BUT IT LEADS US TO CONSIDER
WHEN DO WE START THE TREATMENT
AND IN WHICH PATIENT.
THERE ARE CERTAIN PATIENTS
THAT HAVE BEEN APPROVED FOR
THE MODULATOR THERAPY BUT WE
DON'T SEE THAT TOGETHER WITH
THE PROTEINS.
SO IT MAKES US QUESTION AT
WHAT POINT DO WE INITIATE
THERAPY.
AND TO THE CONVERSE, WE HAVE
PATIENTS THAT ARE PRESENTING
SOME SPECTRUM OF CFPR BUT
THEIR SYMPTOMS ARE FINE.
SO I THINK THE TREATMENT AND
STUDY OF LONG-TERM RISK BEN
PHYSICIAN ARE REALLY ONE OF
RESEARCH AND EXPERIENCE.
>> THANK YOU, AT THIS TIME I
WOULD LIKE TO THANK THE
PLENARY SPEAKERS FOR THEIR
TIME AND PERSPECTIVE.
WE WILL MOVE ON FROM SESSION 1
BUT I DO ENCOURAGE THOSE
PARTICIPATING IF YOU HAVE A
QUESTION THAT WAS NOT
ANSWERED, YOU CAN
DIRECT-MESSAGE THE SPEAKER OR
YOU CAN POST IT IN THE CHAT
AND THE SPEAKERS CAN ANSWER IT
LIKE THAT.
THANK YOU.
>> ALL RIGHT, SO THANKS
EVERYBODY FOR JOINING OUR NEXT
SYSTEM, WHICH IS THE MOUSE
MODELS FOR UNDERSTANDING THE
HIGHLY EFFECTIVE MODULATOR
THER APY.
OUR NEXT SPEAKER WILL BE CRAIG
HODGES AT THE CASE WESTERN
RESERVE UNIVERSITY.
AND WE HAVE A SLIDE UP FOR HOW
HAD MODELS FOR CF, NOT SURE I
SEE MY CO-HOST.
>> I AM HERE.
>> ARE REINTRODUCING ALL THE
SPEAKERS AT ONCE OR --
>> ONE BY ONE, I THINK.
>> OKAY, SO CRAIG, GO AHEAD.
>> ALL RIGHT, THANK YOU VERY
MUCH, I WOULD LIKE TO THANK
THE ORGANIZERS FOR THE
INVITATION TO SPEAK TODAY AND
AS MENTIONED, WE ARE FOCUSED
ON USING THE MOUSE MODEL FOR
HIGHLY EFFECTIVE MODULATOR
THERAPY.
SOME OF THE ADVANTAGES SHOWN
HERE IN THIS SLIDE, THE
ABILITY TO CONTROL MOST
CONDITIONS WITH A
DISTINCTIVELY GENETIC
BACKGROUND, A SHORT TIME TO
SEXUAL MAT TUTOR, PRODUCING
MANY GENETICALLY IDENTICAL
OFFSPRING, A FULLY SEQUENCED
GENOME.
AND AS FAR AS THE MOUSE AS A
MODEL FOR CYSTIC FIBROSIS, THE
PHENOTYPE SHOWS THE ASPECTS OF
ALMOST EVERY PHENOTYPE OF THE
DISEASE.
WHILE IN LATE STAGE, ONE OF
THE DISEASES IS NOT OBSERVED
IN THE MICE WITH LUNG DISEASE
BUT THERE ARE SIMILAR SO THE
MAIN QUESTION HERE TODAY IS
ARE MICE USEFUL IN THE STUDY
OF CFTR MODULATORS?
THE FIRST POINT I WANT TO MAKE
IS HUMAN AND MOUSE CFTR ARE
NOT IDENTICAL.
SO ON THE GENE LEVEL, THEY
HAVE A 82 PERCENT SEQUENCE
THAT IS IDENTICAL IN THE
CODING REGION.
FROM THE HUMAN STANDPOINT,
AMINO AS SAID IS 78 PERCENT
SIMILAR.
SO IS IT ENOUGH IN THE MOUSE?
SOME STUDIES SHOW THAT IT DOES
NOT POTENTIATE THE CFTR.
THERE IS ONE STUDY, AND THERE
ARE MANY BUT LOOKING AT THE
CFTR CELLS, HUMOR MOUSE, THE
STRONGEST RESPONSE FROM HUMAN
FACTORS.
AND GENISTEIN CONTROLLED THIS
VERY WELL.
ON THE OTHER HAND, WE FOUND 15
CORRECT TORSION RESCUED HUMAN
AND MOUSE CFTR.
HOWEVER TESTING THE HUMAN TO
MOUSE CFTRS HAVE BEEN
OVEREXPRESSING RATHER THAN
USING PRIMARY CELLS IN THE
MOUSE.
MY LAB HAS BEEN INTERESTED IN
USING THE CFTR MODULATORS AND
INTESTINAL ORGANISMS.
CFTR IS PREDOMINANTLY
EXPRESSED AT THE APICAL POINT
OF THE STEM CELLS WHERE
FORSKOLIN DRIVES THE SECRETION
AND IF CFTR IS NOT EMPHASIZED,
NO EXPRESSION IS OBSERVED.
I AM GIVING AN EXAMINER HERE
OF NONCF ANIMALS AND ABOUT
FORSKOLIN IS ADDED, YOU CAN
SEE THAT THEY SWELL LIKE
BALLOONS.
THIS HAPPENS VERY QUICKLY,
LIKE IN TEN MINUTES AND WE CAN
MEASURE HOW MUCH THEY EXPAND.
AND WHEN WE DO THAT, WE GET A
FIGURE LIKE THIS IN WHICH THE
PERCENT AREA NORMALIZED IS
INCREASING OVER TIME.
THIS FIGURE SHOWS ADULT F508
MOUSE EMULATERS AND WHAT YOU
WILL SEE IS THE NO TREATMENT
AND THE VX-'70 GROUP ARE
IDENTICAL SUGGESTING THAT YES,
MICE WHO DON'T HAVE THE
SYMPTOMS DON'T RESPOND TO THE
THERAPY, HOWEVER THERE IS A
RESULT FROM THE VX-445 AND 661
ABOVE.
AND USING BOTH CORRECT TORSION
ON THE MOUSE HAVE BEEN
OBSERVED.
SO DOES CFTR MODULATORS WORK
ON THE MOUSE CFTR?
YES.
BUT THERE IS DIFFERENCES IN
GATING.
CORRECT TORSION HAVE A VERY
SIMILAR RESPONSIVENESS IN
HUMANS BUT WHAT ABOUT THE
OTHER CFTR MODULATORS?
THIS MAY DEPEND ON THE HUMAN
PART BUT WE DECIDE TO BUILD A
MODEL THAT EXPRESS BOTH MOUSE
AND HUMAN CFTR.
WE ACCOMPLISHED THIS WITH A
RANDOM SEARCH OF THE WHOLE
258KB HUMAN CFTR GENE THAT WAS
CONTAINED IN THE ARTIFICIAL
CHROMOSOME ESPECIALLY SO MANY.
THIS SHOWS THAT IT WOULD BE
EXPRESSED IN THE CFTR PROMOTER
AS WELL AS MOST NONREGULATORY
FUNCTION.
SO THE CF MOUSE BACKGROUND, IT
EXPRESSES THE CFTR IN MAIN
TISSUES AND DISPLAYS THE
FUNCTION IN AIRWAY AND
INTESTINE.
THIS LEADS US TO CREATE
SEVERAL HUMAN IMPLEMENTATIONS
IN HOPES THEY WOULD REACT IN
VIVO SIMILAR TO HUMANS.
THE TWO MUTATIONS I WILL TALK
ABOUT TODAY ARE SHOWN HERE,
THE HCFTR AND THE HCFTRG551D.
THAT IS SHOWN HERE.
WHILE THE WILD TYPE OF HUMAN
HCFTR SHOWED THE FUNCTION IN
THE MOUSE, IN THE HUMAN
MUTATION, IT SHOWED VERY
LITTLE.
SO OF COURSE WE WANTED TO USE
FTA APPROVED DRUGS, VX-770 OR
661 ON THE MOUSE TO SEE IF WE
COULD CORRECT THIS HUMAN CFTR
FUNCTION.
FIRST WE TESTED THE MODULATORS
IN VITRO USING THE AFORE
MENTIONED INTESTINE ORGAN
MODEL IN THE MICE.
HERE IS AN EXAMPLE OF THE
FUNCTION IN THE INTESTINE
ASSAY AND IF THERE IS NO
TREATMENT, THESE DO NOT SWELL
AT ALL EVEN IN A 24-HOUR
PERIOD.
HOWEVER IF THEY ARE PUT IN IN
24 HOURS, THEY DISPLAY
RESTORED CFTR FUNCTION.
AND SHOWING HERE HAVING THE
STRONGEST EFFECT AND WHILE I
DON'T HAVE TIME TO PRESENT ALL
OF THE DATA, I CAN SAY THE
VX-770 WORKS SIMILARLY ON THE
DEHAO*UPLIZED MOUSE.
WE THEN SHOW THE HCFTR
FUNCTION IN THE MOUSE FOR
THREE DAYS AND IMPROVED
FUNCTION, USING CHAMBERS FOR
MICE THAT WERE NOT TREATED IN
BLACK AND WERE TREATED IN RED.
SO SHOWN HERE WITH THE ARROW,
SHOULD INCREASE THE SHORT KIRK
FUNCTION AND THAT IS WHAT WE
FOUND HERE.
WHEN WE ADDED THE HCFTR IN AT
LEAST FOUR MICE, IT SHOWS THAT
IT IS VERY STRONG IN WILD TYPE
MICE, THE HUMAN CFTR MICE WITH
THE AGAIN BUT NOT MUCH CHANGE
IN THE VX-770 OR 661 MICE.
HOWEVER WHEN WE ADD THE
IMPORTANT MODULATORS, YOU TO
SEE N INCREASE IN THE FUNCTION
ALMOST TO THE LEVEL OF THE
WILD TYPE MICE.
THIS IS SUGGESTED THESE
MUTATIONS CAN BE CORRECTED IN
VIVO USING THIS MODEL.
NOW, WITH EVERYTHING I HAVE
SHOWN YOU BEFORE, WE WANTED TO
ASSESS THE FUNCTION OF THE
AIRWAY.
SO WE LOOKED AT THE NASAL
POTENTIAL DIFFERENCE AND IT
WAS MEASURED BEFORE AND AFTER
THE ADDITION OF CHLORIDE-FREE
SOLUTIONS INCLUDING PORCELAIN
IN THE MOUTH.
NONCFTR SHOWED A RESPONSE IN
THE WILD TYPE AND HCFTR MICE,
HOWEVER THERE IS NO RESPONSE
IN THE TWO MUTATED MICE AND
THIS IS AN IN VIVO ASS AY, I
WANT TO SAY.
BUT ONCE THEY WERE TRANSMITTED
FOR THREE DAYS, WE SEE A
DIFFERENCE IN THE RESPONSE FOR
THE CORRECTED DIFFERENCE
SHOWING THE MICE DO RESPOND IN
VIVO TO THE MODULATORS.
SO WE NEED TO KEEP IN MIND
THERE ARE STILL CONDITIONS NOT
POINTED OUT IN THE MODULATOR.
I WOULD ALSO POINT OUT WE HAVE
CREATED SPLICING MUTATION WITH
THE F508D EL AND G55 AND
HOPEFULLY THIS WILL BE
IMPORTANT IN THE FUTURE OF
MOUSE MODELS.
SO NOW TO ANSWER THE QUESTIONS
USING MOUSE MODELS, WE CAN
ADDRESS IMPORTANT POINTS.
ONE IS THAT IT ALLOWS THE
MOUSE TO DEVELOP OF HUMAN TO
ADULT.
THE CF MOUSE SHOWN HERE ARE
LITTERING FOR THE CF AND A
NONCF MOUSE.
THE SMALLER BEING THE CF
MOUSE.
HERE IS AN AVERAGE WEIGHT OF
POPULATION OF MICE FROM DAY 10
TO 40 BUT WE KNOW THIS
REDUCTION IN WEIGHT ACTUALLY
EXTENDS ALL THE WAY BEFORE
BIRTH IN UTERO.
WE KNOW IF WE RESTORE THAT
HALFWAY THROUGH IN THE MOUSE
MODEL SHOWN HERE IN RED, WE
CORRECT THIS.
WILL MODULATORS HAVE THE SAME
EFFECT ON THE HAO*UPLHUMANIZED
MOUSE MODEL?
POTENTIALLY AND NOW WE HAVE
MORE INFORMATION ON WHAT IT
WILL CORRECT DURING THE
LIFETIME OF THE MOUSE.
AND THE OTHER ASPECT IS MOUSE
LITTERS WILL BE ABLE TO
ADDRESS WHETHER THERE IS ANY
CHANGE IN UTERO.
THE MOUSE CAN BE USEFUL IN
STUDYING THIS VERY QUICKLY.
ALSO WHAT DOES LONG-TERM OF
MODULATORS LOOK LIKE?
DOES THIS DECREASE OVER TIME
WHEN THE CFTR GETS AWAY TO
TOTAL ABSENCE?
THE MOUSE HAS A 2-YEAR
LIFESPAN, THEY ARE LESS
EXPENSIVE AND QUITE SMALL
COMPARED TO OTHER ANIMAL
PATIENTS.
ANOTHER QUESTION IS WHAT IS
THE EFFECT OF THE MODULATORS
ON INTESTINAL SYMPTOMS.
DATA SHOWING AFTER SIX MONTHS,
THE PATIENT SHOWED NO CLINICAL
CHANGE IN SYMPTOMS SUGGESTING
WHILE LUNG FUNCTIONS IMPROVE,
THE GI SYMPTOMS MAY HAVE
LITTLE TOLL NO IMPACT.
THE MOUSE MAKES THIS A GOOD
MODEL FOR TESTING AND ONE LAST
QUESTION WE MIGHT BE ABLE TO
ASSIST WITH CONCERNING THE
IMPACT OF MODULATORS IS WHAT I
CALL THE UNDER STUDIED MAN
TESTATIONS AND THESE ARE VERY
IMPORTANT.
ONE EXAMPLE IS SLEEP.
FOR CLINICIIANS WHO ARE
STUDYING PATIENTS WITH CF,
THEY KNOW THERE IS A SLEEP
DISRUPTION.
SOME OF MY COLLEAGUES THAT
HEAR THE CASE HYPOTHESIZE THAT
LOSS OF CFTR CAUSES THE
DISRUPTION OF THE GENE
EXPRESSION REGULATION AND
FOUND THIS WAS INDEED THE CASE
IN CF MICE.
THEY HAVE EXPANDED ON THIS
INITIAL SUBJECT AND FOUND THAT
SIMILAR TO CF PATIENTS, THE
MICE SHOWED ALTERED SLEEP
PARTIES.
HERE IS SOME OF THE DATA THAT
HAS NOT BEEN PUBLISHED YET, SO
WITH THE CF MOUSE OVER 14
DAYS, THE CYCLES INDICATED
HERE BY THE WHITE AND THE
BLACK MARK.
THE PLAQUE LINES ARE THE
ACTIVITY IN THE MOUSE DURING
THE SAY.
SINCE THEY ARE NOT TURN, YOU
WILL SEE LESS ACTIVITY IN THE
DARK.
HOWEVER, ACTIVITY IS LESS
CONTAINED IN THE DARK CYCLE
AND STARTS BEFORE THE DARK
CYCLE IS OVER SHOWN HERE.
IN ADDITION, WHEN THE MICE ARE
SWITCHED TO A CONSTANT DARK
CYCLE INDICATED BY ONE DARK
BLACK BAR, THE NORMAL PART
PATTERN DECREASED THEIR
ACTIVITY AND SHORTENED THEIR
CYCLE.
BUT THE DELTA F MICE HAVE A
DIFFERENT OUTCOME AND THAT IS
SHOWN HERE ON THE RIGHT.
TO SEE THE CIRCADIAN RHYTHM
CORRECTED BY THE MODERATE
LATER, THE ABILITY TO CONTROL
THE MICE SHOULD ACCELERATE AND
FACILITATE RESEARCH.
I WOULD LIKE TO THANK AND
ACKNOWLEDGE ALL THE PEOPLE
INVOLVED IN THE RESEARCH AND
IF YOU ARE INTERESTED IN MORE
INFORMATION, PLEASE CONTACT
ME.
THANK YOU VERY MUCH.
>> OKLAHOMA, SHALL REMOVE ON
TO THE NEXT TALK?
THANK YOU, CRAIG.
SO OUR NEXT SPEAKER IS SUSAN
BIRKET AND WHILE I DON'T HAVE
HER TITLE, WE KNOW SHE WILL BE
SPEAKING TO US ABOUT THE MOUSE
MODEL.
PLEASE PROCEED.
>> THANK YOU.
ITCH MY OWN SLIDES IF YOU NEED
ME TO.
>> NO, WE'RE GOOD.
>> SO THANK YOU FOR HAVING ME
TO TALK ABOUT THE RAT MODELS
FOR HIGHLY EFFECTIVE MODULATOR
THERAPY.
NEXT SLIDE.
SO THE RAT AS A MODEL OF CF
AIRWAY DISEASE WAS GENUINE
RAPED BACK IN 2011.
THE RAT SPECIES HAS SEVERAL
ADVANTAGES.
THEY ARE LARGER AND LIVE A
LITTLE LONGER THAN MOUSE WHICH
ENABLE A LONGER STUDY.
IT ENABLES INDEPTH OF THEERAPY
AND TESTING AND THE
TRADITIONAL MODELS INCLUDING
IN THE LUNG WHICH MEANS THERE
IS A WEALTH OF DATA FROM
DECADES AGO ABOUT SORT OF THE
BASELINE EFFECT OF THE WILD
TYPE BUT ALSO MEAN THERE IS AN
ABUNDANCE OF ANTIBEEN ODIES TO
USE IN THE CONDUCTOR STUDIES.
IT IS VERY EASY TO MOVE BACK
AND FORTH BETWEEN
FIREMANACALOGICAL AND
TOXICOLOGY STUDIES AS WE MOVE
FORWARD WITH THE NOVEL
STUDIES.
SO WE INITIATED THIS MODEL
WITH THE CF KNOCKOUT NULL
WHICH HAS THE EXPRESSION AND
LEADS TO A STOP IN EXON4 AND
5.
NEXT SLIDE.
SO WE FOCUSED OUR STUDIES
PRIMARILY ON THE LUNG AND THE
MANIFESTATION OF MUCOUS
ABNORMALITY AS THE RAT AGES.
WE FOCUSED OR STUDY PRIMARILY
ON TRANSPORT OF THE LARGE
AIRWAYS AND WHAT WE FOUND WAS
THAT AT UP WITH MONTH OF AGE,
THE WILD TYPE AND CF RAT ARE
VERY DISSIMILAR.
AS WE MOVE TO THREE MONTHS OF
AGE IN THE MIDDLE OF THE
GRAPH, YOU CAN SEE THE CF IN
THE RED SCARE THAT SEPARATES
FROM THE WILD TYPE A EFFECTIVE
IN TRANSPORT AND BY SIX MONTHS
OF AGE, IT HAS AIRWAYS
SEVERELY DELAYED AT SIX MONTHS
OF AGE AS WELL AS HIGHLY
DEFECTIVE.
SO WE LOOK AT THE RED STAGE
INDICATED BY RED ARROWS.
MANY OF OUR STUDIES START AT
TWO MONTHS OF AGE AND PROGRESS
TO SIX MONTHS OF AGE IN WHICH
THE MUCOUS IS VERY STATIC AND
EVASIVE.
NEXT SLIDE.
SO ONE OF THE PRIMARY OUTCOMES
THAT WE HAVE LOOKED AT IS
INFECTION IN THE LUNG AND WE
STARTED WHEN WE INFECTED
KNOCKOUT RATS AT TWO MONTHS OF
AGE, WE SEE HIGH RATES OF
INFECTION, NO DIFFERENCE.
BY DAY 7 OF INFECTION, THE
CFES HAVE SIGNIFICANTLY
INCREASED IN THE WILD TYPE.
AT TWO MONTHS OF AGE, HAVE
CLEAR LUNGS BY DAY 28
INDICATING WHATEVER EFFECTS
THE LUNGS WERE SUBJECTED TO,
THE INFECTION TOTALLY RESOLVED
BY THE END OF THE EXPERIMENT.
ON THE RIGHTHAND SIDE OF THE
SLIDE, WE SEE A DIFFERENCE
WHEN RATS ARE INFECTED AT SIX
MONTHS OF AGE.
AS MENTIONED THE DOTTED LINE
INDICATES THE CURRICULUM, AT
AGE 9, DAY 7, IT HAS
COMPLETELY REMOVED THE
INFECTION.
DAY 28, THE CF IN THE LUNG IS
EQUAL TO THE KNOCKOUT.
SO IF YOU LOOK AT THE
HISTOLOGY BELOW, YOU CAN SEE
THE WILD TYPE HAS CLEAR BONES
END KATE HILLARY CLINTON ANY
DAMAGE BUT THE KNOCKOUTS
SPECIFICALLY DEVELOP
AATTACHMENTS AND BY DAY 28, WE
CAN SEE THE SMALL AREAS THAT
COMPLETELY OCCLUDED.
NEXT SLIDE.
SO HOW CAN WE USE THIS.
>> Moderator: DEL TO PREDICT
THE PATIENT'S RESPONSE TO
THERAPEUTICS?
WE WANTED TO KNOW IF CFR WOULD
CORRECT IN HUMANS LIKE THE
MOUSE COULD YOU TELL COMES
AFFECTED IN THIS MODEL.
SO TO DO THAT, WE TOOK THE
HUMAN CFTR WITH THE EXON2,
INCERTAIN THIS GENE INTO THE
RAT GENOME SO THIS IS
ESSENTIALLY A GENE, BEHIND THE
LOADER AND ANDOGENOUS EXON1
AND INTRON1.
WE WENT RIGHT TO THE REPORTS
THAT IT MAY NOT BE RESPONSIVE
TO EITHER.
NEXT SLIDE.
SO THE DATA THAT I AM
PRESENTING HERE IN THE SLIDE
IS PRIMARILY AIR EXPRESSION OF
HG551D, THE HUMANIZED VERSION.
WE HAVE ALSO LOOKED AT THE
CORRECTIONS AND SEE THIS IS A
GLOBAL INFECTION OF THE
HUMANIZET GENE.
AS WE START AT THE TOP LEFT,
WE LOOKED AT THE MRNA.
WHEN YOU USE RAT SPECIFIC
SEQUENCES, WE HAVE VERY LITTLE
RAT MRNA EXPRESSION IN THE TWO
COMPARED TO THE WILD TYPE.
WHEN YOU USE THE HUMAN CORRECT
TORSION, YOU CAN SEE
SIGNIFICANT ABUNDANCE COMPARED
TO THE WILD TYPE AND THE
KNOCKOUT AND HERE WE CAN SEE
THE DEFECT EXPRESSES
APPROXIMATELY AS MUCH
CFTR MRNA AS THE WILD TYPE
SPECIFIED TO THE CFTR IN THE
KNOCKOUT.
AND AS WE HOOK AT THE
EXPRESSION, COMPARED TO THE
WILD TYPE, WE HAVE SIMILAR
LEVELS OF CFTR EXPRESSION IN
THE THOSE COMPARED.
SO WE HAVE IT EXPRESSED
APPROPRIATELY IN THE CELL
TYPE.
WE ALSO LOOKED AT THE TRACHEA
AND ASSESSED THE CFTR ACTIVITY
IN THE GRAPH AT THE BOTTOM.
THE WILD TYPE AT THE TOP, HIGH
CFTR ACTIVITY AND THE PACE
LINE STARTING AROUND 350 THAT
IS PARTIALLY DECREASED IN IT
THE BLOCK IN THE PANELS AND
THEN INCREASED BY THE CFTR AND
YOU CAN SEE ON THE RIGHT SIDE
THERE ARE HARDLY ANY OR
MINIMAL EFFECTS.
IN THE RED SQUARES, WE HAVE
THE KNOCKOUT RATS THAT START
VERY LOW AT PACE LINE AND HAVE
NO CHANGE WHATSOEVER WITH
EITHER ADDED IN.
BUT WHEN WE ASSESS THE
HUMANIZED EXPRESSION, WE SEE
LOW STARTUP ACTIVITY AT
BASELINE BUT INCREASED IN A
DOSE-DEPENDENT MANNER FOR
EITHER FACTOR.
NEXT SLIDE.
AND WHEN WE DOSE THESE RATS
SYSTEMICALLY FOR 14 DAYS WITH
VX-770, WE SAW A DIFFERENCE
AND ABLE TO SEE AN INCREASE IN
THE ACTIVITY AND THE GRAPH AT
THE TOP, YOU HAVE THE DELTAS
FROM BASELINE AND WHEN YOU
LOOK AT THE SUMMARY DATA, THE
TWO GRAPHS ON THE BOTTOM, YOU
CAN SEE UNTREATED IT IS VERY
LOW COMPARED TO THE WILD TYPE
AND INCREASES TO ABOUT
50 PERCENT WILD RAT ACTIVITY.
NEXT SLIDE.
AND WE WANTED TO KNOW IF WE
CAN RESTORE AS SHOWN IN THE
LAST SLIDE.
TO DO THAT WE USE
MICROSPECTOMETRY AND SHOW THE
TRANSPORT AND VISCOSITY OF THE
MUSIC CAN YOU SAY.
BOTH ARE RESTORED IN THE G551D
AND IN THE BOTTOM SQUARE, THE
TRANSPORT AND EXPECTORATION
AFTER THE ADDITION OF
IVACAFTOR.
SO WE WANT TO KNOW HOW THIS
INFLUENCES THE INFECTION
IN THIS CASE ON THE BOTTOM, WE
SAW A DECREASE OF CFUs IN THE
IVACAFTOR-TREATED RATS AND A
DECREASE OF NEUTROPHILS.
WE ALSO SAW THAT IN THE
IVACAFTOR-TREATED RATS, ABOUT
50% OF THE BACTERIA CONVERTED TO
A NON-MUCOID PHENOTYPE.
IN THE CHRONIC INFECTION, WHICH
ACTUALLY INITIATED -- OH, I'M
SORRY, THIS IS A PRE-TREATMENT
INFECTION, WE INITIATED
IVACAFTOR ABOUT SEVEN DAYS
BEFORE WITH SACRIFICE AT DAY 14.
AGAIN WE SAW CFUs, DECREASE
ALTHOUGH NOT STATISTICALLY IN
THE PERCENT NEUTROPHILS.
HERE'S THE CHRONIC INFECTION
DATA WHERE WE INFECTED AT DAY
ZERO AND BEGAN TREATMENT AT DAY
7 WITH SACRIFICE AT DAY 28.
IN THIS CASE UNFORTUNATELY WE
DID NOT SEE A DECREASE IN CFUs
IN THE IVACAFTOR-TREAT THED RATS
OR DECREASE IN THE PERCENTAGE OF
NEUTROPHILS.
SO FROM THIS WORK, WE CAN
CONCLUDE THAT WE HAVE ACHIEVED
TARGETED INSERTION OF THE HUME
NIEZED G551D SEQUENCE WHICH
APPEARS TO BE EXPRESSED
APPROPRIATELY TO IVACAFTOR.
THE TREATMENT CORRECTS CFTR
CURRENT MUCOCILIARY TRANSPORT
AND ALTHOUGH IT DOES NOT LEAD TO
COMPLETE ERADICATION IT DOES
SEEM TO AMELIORATE THE FORCE OF
DISEASE.
FUTURE STUDIES WILL CONTINUE TO
LOOK AT THIS IN DEPTH TO
UNDERSTAND IF WE CAN USE HIGHLY
EFFECTIVE MODULATORS TO CONTINUE
TO DECREASE INFECTION.
MOVING FORWARD, SO WE CLEARLY
HAVE SOME UNMET NEEDS IN THIS
COMMUNITY AND WE THINK THE RAT
CAN ADDRESS THESE AS WELL.
WE'VE CREATED SEVERAL ADDITIONAL
MODELS OR IN THE PROCESS OF
CREATING ADDITIONAL MODELS.
THE FIRST ONE IS A G542X
MUTATION WHICH IS A POINT
MUTATION, THIS IS THE RAT GENOME
BUT IT HAS ONLY THE POINT
MUTATION SO IT PRESERVES ALL THE
SEQUENCES SURROUNDING.
THIS MODEL WILL BE USED TO TEST
BOTH MODEL AGENTS AND GENE
REPLACEMENT STRATEGIES MOVING
FORWARD.
SO WHAT ARE THE GAPS AND THE
LONG TERM QUESTIONS THAT THESE
RAT MODELS CAN HELP ADDRESS.
[TEST]
FOR EXAMPLE, I HAVE
NON-CORONAVIRUS AND CORONAVIRUSF
AIRWAYS, ONE CAN INACTIVATE CFTR
JUST IN THAT CELL TYPE AND STUDY
DISEASE PROGRESSION OR ONE CAN
REACTIVATE CFTR WITHIN THOSE
CELL TYPES ON A CF BACKGROUND
AND FOR EXAMPLE MODEL A GENETIC
THERAPY THAT'S TARGETING
CORRECTION OF CFTR IN EITHER OF
KNOWS TWO CELL TYPES.
NOW, TO MOVE ON TO THE RELEVANCE
OF THESE MODELS TO MODULATE
THERAPY, WE'VE DEVELOPED A GFF1D
MODEL IN THE ABSENCE OF
MODULATOR, IT DEVELOPS AIRWAY
DISEASE AND GLAND PLUGGING YOU
MUCH LIKE KNOCKOUT FERRETS AS
COMPARED TO NORMALS.
IF THEY'RE MAINTAINED, IT
PREVENTS LUNG DISEASE AND
PANCREATIC DISEASE.
NOW WHEN THESE ANIMALS ARE
REMOVED FROM MODULATOR, THEY
BECOME COLONIZED, HERE SHOWN AS
THE AMOUNT OF BACTERIA BOTH IN
THE LUNG WHEN THE ANIMALS ARE
EUTHANIZED ON THE RIGHT, OR THE%
OF VARIOUS TAXONS WITHIN THE
LUNG, DIFFERENT TYPES OF
BACTERIA.
SO THEY GET COLONIZED WITH TIME,
AND ON VX770 WE CAN RECOVER
ABOUT 75% OF CFTR ACTIVITY HERE
IN GREEN COMPARED TO WILD TYPE.
NOW, THIS MODEL IS PARTICULARLY
RELEVANT AND IMPORTANT IN
STUDYING BOTH THE ONSET AS WELL
AS THE REVERSIBILITY OF DISEASE
PROCESSES USING THESE MODULATOR
THERAPY.
WE'VE ALSO LEARNED THAT THESE
ANIMALS AS THEY AGE CAN
SPONTANEOUSLY ACQUIRE MUCOID
PSEUDOMONAS.
THESE ARE MUTATIONS WITHIN
PSEUDOMONAS THAT OCCUR MOST
OFTEN WITHIN HUMANS, AND IN THIS
PARTICULAR CASE, IN THE LUNG
TISSUE, NEARLY ALL THE BACTERIA
RESIDENT WITHIN THE CF -- THIS
IS DELTA F508, WAS PSEUDOMONAS.
NOW WE CAN STUDY BOTH THE ONSET
OF DISEASE PROCESSES AS WELL AS
THE ABILITY OF MODULATORS TO
REVERSE THOSE PROCESSES AS SHOWN
HERE.
THIS IS AN IMAGING OF A WILD
TYPE TRACHEA, MONITORED OVER
TIME MOVING UP.
AND HERE WE'RE COMPARING CF
FERRETS, EITHER ON MODULATOR
THAT'S BASELINE OR REMOVED AT
ONE, TWO OR THREE WEEKS HERE IN
YELLOW, ORANGE AND PURPLE, AND
YOU CAN SEE THERE'S A DECLINE IN
CLEARANCE WITH TIME.
THEN THESE ANIMALS WERE PUT BACK
ON MODULATOR, AND YOU CAN SEE
THIS REVERSE.
THIS IS JUST QUANTIFYING THAT AS
PERCENT REMAINING IN THE
TRACHEA.
NOW, THIS IS A VERY SHORT
EXPERIMENT OF ABOUT A MONTH, AND
IT'S UNCLEAR WHETHER OR NOT THE
EXTENSIVE DISEASE HERE SEEN IN
THIS REMODELED CF AIRWAY IS
REVERSIBLE WITH HIGHLY EFFECTIVE
MODULATOR THERAPY.
SO IT WOULD BE IMPOSSIBLE AT
LEAST FOR ME TO TALK ABOUT THE
EFFECTIVENESS OF MODULATORS
WITHOUT TALKING ABOUT PANCREATIC
DISEASE STATES.
PANCREATIC INSUFFICIENCY IS
KNOWN TO LEAD TO CF-RELATED
DIABETES AND THIS WORSENS LUNG
FUNCTION, AND WE'VE STUDIED
PANCREATIC RETENTION AND
PANCREATIC FUNCTION ON THESE
TYPES OF MODULATORS IN BOTH THE
G551D AND IF THEY'RE REMOVED
FROM THE MODULATOR, DISEASE
PROGRESSES AND YOU GET THE
TYPICAL FIBROSIS WITHIN THE
PANCREAS.
SO HOW DOES THE AGE OF
PANCREATITIS ONSET IMPACT THE
DEVELOPMENT OF CFR D?
SO WE DID THE FOLLOWING
EXPERIMENT IN WHICH WE BIRTHED
G551D FERRETS ON VX770 AND KEPT
IT ON IT FOR FOUR MONTHS AND
THEN REMOVED THE VX-770 AND
FOLLOWED THE GLYCEMIC STATUS
WITHIN THESE FERRETS.
WHAT WE SAW WAS THE GROUP THAT
CAME OFF VX-770 VERY EARLY HAD A
GLYCEMIC CRISIS THAT IS VERY
TYPICAL OR IS ALWAYS SEEN WITHIN
CFTR KNOCKOUT FERRETS BUT THE
GROUP THAT WAS OLDER WHEN THEY
CAME OFF VX-770 DID NOT HAVE
THIS CRISIS.
THIS IS FAST ONE OUR
POSTPRANDIAL BUT WHAT YOU CAN
SEE IS THE GROUP THAT CAME OFF
LATE PROGRESSED TO THE POINT OF
WORSE GLUCOSE OR GLUCOSE
HANDLING AS THEY AGE, AND SO
FIVE MNTS AF MONTHS AFTER DETERN
OF THE MODULATOR, ONE CAN SEE
THE ANIMALS THAT CAME OFF EARLY
IN LIFE ACTUALLY FAIRED BETTER
AND WERE CLASSIFIED AS
INDETERMINANT AS THOSE THAT CAME
OFF LATER IN LIFE WERE
CLASSIFIED AS CFR D.
THESE ARE JUST THE NUMBERS IN
THOSE VARIOUS GROUPS, SHOWING
THAT NONE THAT CAME OFF EARLY
ACTUALLY HAD A CFR D PHENOTYPE.
SO AGE OF PANCREATIC ONSET
IMPACTS LONGER TERM ISLET
FUNCTION AND ACQUISITION OF CFR
D STATE, AND THE IMPACT OF THESE
CHANGES ON THE LUNG ARE
CURRENTLY UNKNOWN BUT WE'RE
HOPING TO BE ABLE TO ADDRESS
THIS THROUGH MORE STUDIES.
ANOTHER -- ANOTHER FINDING THAT
WE HAD IS THAT WHEN ANIMALS WERE
REMOVED FROM VX-770 EARLY IN
LIFE, THERE WAS SIGNIFICANTLY
INCREASED HEALTH PROBLEMS THAT
REQUIRED TERMINATION OR REQUIRED
EUTHANASIA OF THE ANIMALS.
THIS OCCURRED IN TWO DIFFERENT
PHASING.
ONE MORE IMMEDIATE FOLLOWING
REMOVAL WHICH INVOLVED
OBSTRUCTION RECTAL PROLAPSE AND
ANOTHER INVOLVING SEVERE
ENTERITIS AND ELEVATED LIVER
FUNCTION TESTS.
THIS IS JUST AN EXAMPLE OF THE
ONTOLOGY, SLOUGHING VILLI,
SIGNIFICANT AMOUNT OF
INFLAMMATION AND ANIMALS THAT
HAD THIS PHENOTYPE SUCCUMBED TO
DISEASE AT THIS TIME POINT HAD
ELEVATED LIVER FUNCTION TESTS.
ANOTHER FINDING THAT WE'VE HAD
IN REARING THESE ANIMALS ON
VX-770 IS THE FACT THAT
COMPARING ONES THAT HAD BEEN ON
IT FOR LIFE OR TERMINATION AT
ONE MONTH OF AGE, WE CAN SEE
HERE THAT MOST ANIMALS BUT NOT
ALL THAT ARE PLAIN TA MAINTAINEE
ONE TO TWO-MONTH TIME POINT ARE
PANCREATIC-SUFFICIENT.
OBVIOUSLY ONCE THEY COME OFF,
LOSE PANCREATIC FUNCTION, THIS
IS FECAL LASTASE I'M SHOWING
HERE BUT IN THIS PARTICULAR
EXAMPLE, THESE FOUR ANIMALS THAT
ARE DOWN HERE CLASSIFIED AS
PANCREATIC-INSUFFICIENT,
RECOVERED PANCREATIC FUNCTION
LATER IN LIFE.
SO IVACAFTOR TREATMENT OF
HOMOZYGOUS G551D FERRETS ONLY
PARTIALLY PROTECTS THE PANCREAS.
I THINK THIS IS IMPORTANT WHEN
CONSIDERING THAT PARTIAL
PROTECTION IS PROBABLY ALSO THE
CASE IN THE LUNG, EVEN IF THESE
ANIMALS WERE KEPT ON VX-
770 FOR THEIR ENTIRE LIFE AND IN
UTERO.
YOU CAN SEE HERE JUST AREAS OF
THE PANCREAS THAT HAVE HAD --
THAT HAVE LOST CELL MASS.
ANOTHER ISSUE IS PREGNANCY.
PREGNANCY IS RISING IN CF
PATIENTS AND THIS IS PROBABLY
GOING TO POP UP HERE EVEN MORE.
WE'RE GOING TO HEAR ABOUT THIS
LATER IN THE SESSION, BUT WE
FOUND THAT ANIMALS THAT WERE
TREATED WITH VX-770 IN UTERO AND
POSTNATALLY, BOTH -- FOR LIFE
WERE FERTILE AND COULD GIVE RISE
TO KITS.
WE FOUND THAT WE CAN -- THIS IS
LOOKING AT VX-770 DRUG LEVELS IN
THE MILK AS THEY'RE NURSING
THEIR KITS OR IN THEIR BLOOD,
IT'S ABOUT THREE FOLD LOWER BUT
CAN REAR KITS DELIVERING THE
DRUG THROUGH THE JILL'S MILK.
WE ALSO FOUND OUT THAT G551D
FERRETS THAT WE WERE AGING FOR
LUNG DISEASE AND WERE
PANCREATIC-INSI FUSHT, THEY'D
COME INTO ESTRUS, WE BRED THEM
AND FOUND THIS UNIQUE PHENOTYPE
OF ACUTE FATTY LIVER OF
PREGNANCY HERE, YOU CAN SEE
HEPATOCYTES FILLED WITH LIPIDS,
SIGNIFICANT INFLAMMATION AND
PLUGGING OF THE BILE DUCTS.
SO DRAMATIC STEATOSIS COULD BE
CAUSED BY GALLBLADDER
DYSFUNCTION, NUTRITIONAL DEMAND
AND/OR DEFECT IN FAT EE ACID
OXIDATION CORRELATED WITH LARGER
LITTERS, WHICH IS IMPORTANT
BECAUSE THE INCIDENCE OF ACUTE
FATTY LIVER IN PREGNANCY IS LOW
IN HUMANS, IT'S HIGHER WHEN
THERE ARE TWINS IN UTERO.
THESE NEW PHENOTYPES ARE GOING
TO BECOME INCREASINGLY IMPORTANT
IN PATIENT CARE.
SO THIS BRINGS ME TO MY
KNOWLEDGE GAPS.
IS IN UTERO HIGHLY EFFECTIVE
MODULATOR SAFE AND DOES IT LEAD
TO GREATER PRESERVATION OF ORGAN
FUNCTION POST-NATALLY IN THE
MULTIPLE ORGANS AFFECTED IN CF?
WHAT ARE THE LONG TERM CON
QENSES OF CONTINUOUS TURNOVER OF
EXOCRINE PANCREATIC CELLS WHILE
ON THERAPY?
DOES THIS ENHANCE LUNG
INFLAMMATION DUE TO S SECRETED
CYTOKINES, DOES IT PREDISPOSE TO
DIABETES, EVEN PANCREATIC
CANCER?
AND SHOULD WE BE THINKING MORE
AGGRESSIVELY ABOUT THERAPIES
THAT SHOULD BE USED IN
CONJUNCTION WITH HIGHLY
EFFECTIVE MODULATOR THERAPY IF
THEY'RE REALLY JUST PARTIALLY
EFFECTIVE, EITHER
PROPHYLACTICALLY OR DURING VIRAL
EX-EXACERBATIONS, FOR EXAMPLE.
SO I'LL END THERE.
AND I'D LIKE TO THANK -- THIS
TYPE OF RESEARCH REALLY TAKES A
TEAM.
I'D LIKE TO CALL OUT THE TEAM
FOR MUCH OF THE DATA THAT ARE
PRESENTED HERE.
THANK YOU.
>> JOHN, THANK YOU VERY MUCH.
THERE ARE PLENTY OF QUESTIONS IN
THE BOX WHICH WE CAN CIRCLE BACK
TO LATER ON IF YOU'D LIKE TO
TAKE A LOOK AT THEM.
AND OUR NEXT SPEAKER IS ALSO
FROM IOWA, SARAH ERNST, RESEARCH
ASSOCIATE IN THE UNIVERSITY OF
IOWA.
AND SHE'S GOING TO TALK TO US
ABOUT THE G551D PIG MODEL.
SARAH, PLEASE.
>> OKAY, THANK YOU.
I THINK AS WE CONSIDER CURRENT
AND FUTURE RESEARCH NEEDS, ONE
OF THE QUESTIONS WE'RE ASKING
IS, WHAT ARE THE CHALLENGES IN
THE ERA OF HIGHLY EFFICIENT
MODULATOR THERAPY.
AND WE KNOW THAT FOR THE CASE OF
ESTABLISHED DISEASE, MANY PEOPLE
HAVE BENEFITED FROM MODULATORS.
THEY SEE AN INCREASE IN LUNG
FUNCTION BUT THE CHALLENGE FOR
US IS TO ADDRESS HOW CAN WE HELP
THEM IMPROVE EVEN FURTHER.
THE SECOND CHALLENGE IS THAT
SOME PEOPLE AREN'T ELIGIBLE FOR
MODULATORS.
THIS MAY BE BECAUSE THEIR
GENOTYPE ISN'T COMPATIBLE OR
POSSIBLY BECAUSE THEY'VE HAD TO
DISCONTINUE THERAPY DUE TO SIDE
EFFECTS.
AND A THIRD CHALLENGE IS THAT
NOW, WE HAVE PEOPLE WHO ARE
BEING TREATED WITH MODULATORS
EARLY, BEFORE THE ONSET OF
SEVERE DISEASE AND WE DON'T KNOW
WHAT PROBLEMS MAY DEVELOP FOR
THEM IN THE FUTURE.
SO ONE WAY TO OVERCOME SOME OF
THESE CHALLENGES IS THROUGH THE
USE OF ANIMAL MODELS.
SO OUR GOAL WAS TO DEVELOP A
G551D PIG THAT WOULD BE
MODULATOR-SENSITIVE.
IN THE PAST, WE HAVE DEVELOPED
CFTR KNOCKOUT PIGS THAT LACKED
THE CFTR PROTEIN.
AS WE EVALUATE THE G551D PIG,
I'LL REFERENCE THESE ANIMALS SO
I'M JUST GOING TO PROVIDE A
LITTLE BIT OF BACKGROUND ON THAT
MODEL.
SO THOSE INITIAL CFTR KNOCKOUT
ANIMALS DID NOT HAVE EVIDENCE OF
LUNG DISEASE AT BIRTH, HOWEVER,
THEY DID HAVE HOST DEFENSE
DEFECTS.
WE MEASURED REDUCED ASL PH IN
THE CF ANIMALS.
THIS CONTRIBUTED TO AN INCREASE
IN -- OR A DECREASE IN BACTERIAL
KILLING, AND WE ALSO FOUND THAT
THOSE ANIMALS HAD A DEFECT IN
MUCOCILIARY TRAPT.
TRANSPORT.
SO THIS HOST DEFENSE DEFECTS LED
TO DEVELOPING SPONTANEOUS AIRWAY
DISEASE OVER TIME.
HERE ARE SOME IMAGES FROM THOSE
ANIMALS SHOWING AIRWAY DISEASE
VERY SIMILAR TO HUMANS.
SINCE THIS MODEL LACKS
FUNCTIONAL CFTR, IT MAY NOT BE
USEFUL FOR US TO STUDY THE
CURRENT MODULATORS SO THAT'S WHY
WE DEVELOPED THE G551D ANIMAL.
BUT BEFORE WE STARTED MAKING
THAT PIG, WE DID SOME STUDIES IN
CELLS TO FIND OUT IF G551D WOULD
CAUSE A GATING DEFECT IN PIG
CFTR SIMILAR TO HUMANS.
SO HERE'S AN EXAMPLE OF A PATCH
CLAMP TRACE WHERE WE'RE STUDYING
WILD TYPE CFTR, AND YOU CAN SEE
HERE THAT THE CHANNEL OPENS AND
CLOSES, SO THIS IS A PATTERN FOR
A NORMALLY FUNCTIONING CHANNEL.
WHEN WE REPEAT THESE EXPERIMENTS
WITH THE G551D CFTR FROM PIGS WE
FIND INDEED THEY DO HAVE A
GATING DEFECT AND FORTUNATELY
THIS DEFECT IS PREVENTED OR
RESCUED WHEN WE TREAT THEM WITH
IVACAFTOR.
SO THIS PROVIDED THE EVIDENCE
THAT WE NEEDED TO PROCEED TO
MAKE OUR G551D PIGS.
THE FIRST STEP HERE IS FOR US TO
MAKE HETEROZYGOUS PIGS.
TO THIS, WE USED PIG FETAL
FIBROBLASTS, INFECTED THEM WITH
A VIRAL CFTR TARGETING VECTOR.
SOME OF THOSE CELLS WILL BE
APPROPRIATAPPROPRIATELY TARGETEE
USED THOSE TO MAKE OUR FIRST
HETEROZYGOUS PIGS.
ONCE THEY GROW UP WE CAN MATE
THEM AND THIS PRODUCED OUR FIRST
G551D HOMOZYGOUS ANIMALS.
AS WE STUDY THESE PIGLETS, WE
NEED TO KNOW IF THEY'LL HAVE A
CF PHENOTYPE AT BIRTH.
SO LIKE OUR OTHER ANIMAL -- OUR
OTHER KNOCK WITHOUT MODEL, THEY
DIDN'T HAVE LUNG DISEASE AT
BIRTH, BUT WE DID FIND DISEASE
OF OTHER ORGANS.
SO HERE WE'RE LOOKING AT SOME
HISTOLOGICAL IMAGES FROM THE
PANCREAS.
THE FIRST IMAGES OF WILD TYPE
PANCREAS FOR COMPARISON, OUR
CFGR KNOCKOUT MODEL HAS EXOCRINE
PANCREATIC DESTRUCTION AND SAME
WITH OUR G551D.
SIMILARLY, WE FOUND THAT THESE
PIGS HAVE HEPATOBILIARY DISEASE,
SO YOU CAN SEE A NORMAL WILD
TYPE GALLBLADDER, AND THEN FOR
COMPARISON, OUR KNOCKOUT ANIMAL
HAS A GALLBLADDER VERY REDUCED
IN SIZE AND OUR G551D SHOW A
SIMILAR PHENOTYPE.
ADDITIONALLY WHEN WE STUDIED THE
INTESTINE, WE FOUND THESE
ANIMALS HAVE LETHAL MECONIUM
ILEUS OR INTESTINAL O OBSTRUCTI,
SO THE WILD TYPE, THE BLACK
ARROW IS INDICATING A NORMAL
SPIRAL COLON, OUR CFTR KNOCKOUT
ANIMALS, THE RED STAR IS
INDICATING AN AREA WHERE WE HAVE
INTESTINAL OBSTRUCTION AND IN
OUR CF ANIMALS WE HAVE A MICRO
COLON, WE SEE THE SAME
OBSTRUCTION IN OUR G551D
ANIMALS.
SOL IF OUR GOALSO IF OUR GOAL IA
MODULATOR-SENSITIVE ANIMAL WE
NEED TO MAKE SURE THE MRNA AND
PROTEIN LEVELS ARE WHAT WE HAVE
SEEN AND WE ASK ARE THOSE LEVELS
SIMILAR TO WILD TYPE.
WHEN WE MEASURE MRNA FROM THE
INTESTINE WE FIND THE MRNA
LEVELS ARE SIMILAR BETWEEN G551D
AND WILD TYPE.
THEN WE WENT ON TO TEST WHETHER
OR NOT THIS EXPRESSED CFTR WOULD
BE FUNCTIONAL.
TSO HERE WE'RE LOOKING AT
SHORT-CIRCUIT CURRENT.
WE'VE GOT WILD TYPE HERE IN BLUE
AND IN RESPONSE WE SEE A LARGE
INCREASE SO THIS WOULD INDICATE
CFTR ACTIVITY.
THEN ADDITIONALLY WE ADD
IVACAFTOR, IN WILD TYPE WE DON'T
SEE AN INCREASE, HOWEVER, WHEN
WE LOOK AT G551D IN GREEN, WE
SEE THAT THE G551D INTESTINE HAS
A REDUCED RESPONSE AND WITH
ADDITION OF I' IVACAFTOR, WE SEE
THIS CURRENT IS INCREASED TO
NEAR WILD TYPE LEVELS.
SO THAT'S THE INTESTINE.
WE ALSO WANTED TO LOOK FOR
PROTEIN LEVELS IN THE AIRWAY.
SO HERE WE'RE LOOKING FOR CFTR
IMMUNOSTAINING IN AIRWAY
CULTURES.
FIRST WE'LL LOOK AT WILD TYPE,
CFTR IS STAINED WITH GREEN, SO
THIS IS A NORMAL CFTR EXPRESSION
PATTERN WHERE WE SEE THAT CFTR
IS LOCALIZED TO THE APICAL
MEMBRANE.
OUR CFTR KNOCKOUT ANIMALS LACK
CFTR PROTEIN SO WE DON'T SEE
CFTR STAINING HERE.
THIS IS JUST A GOOD NEGATIVE
CONTROL.
THEN WHEN WE LOOK AT OUR G551D
CULTURES, WE SEE THEY HAVE
NORMAL PROTEIN EXPRESSION.
THEN WE CAN GO ON TO LOOK AT THE
FUNCTION IN OUR AIRWAY CULTURES.
HERE WE'RE LOOKING AT THE CHANGE
IN SHORT-CIRCUIT CURRENT AND WE
SEE THAT FORCE CLIN INDUCED
SHORT-CIRCUIT CURRENT IS REDUCED
IN THE G551D -- THIS FUNCTIONAL
RESCUE WE'VE SEEN IN OUR AIRWAY
CULTURE, WE WANT TO KNOW IF THIS
FUNCTIONAL RESCUE WILL ALSO
RESCUE SOME OF THE HOST DEFENSE
DEFECTS THAT WE'VE SEEN.
HERE WE SEE THE G551D ANIMALS
HAVE A REDUCED ASL PH IN THE
WILD TYPE AND WITH THE ADDITION
OF EYE VO CALF TORE, WE SEE IT
INCREASES.
WE ALSO MEASURED BACTERIAL
KILLING AND WE SEE THAT WHEN WE
LOOK AT THE PERCENTAGE OF
BACTERIA THAT ARE KILLED, THIS
KILLING IS INCREASED WHEN WE ADD
EYE VO CALF TORE.
SO OUR NEXT QUESTION IS WILL
IVACAFTOR RESCUE THE CF
PHENOTYPE?
WE KNOW IN UTERO ADMINISTRATION
OF IVACAFTOR HAS CORRECTED THE
CF PHENOTYPE IN OTHER ANIMAL
MODELS.
AND WE WANT TO KNOW IF IT WILL
WORK IN PIG.
WE WANTED TO KNOW IF THE PIGS
WILL RESPOND TO IVACAFTOR
SIMILAR TO HUMANS, SO FOR THIS,
WE DID DOSE-RESPONSE OF
IVACAFTOR SO WE'RE MEASURING
NORMALIZED TRANS EPITHELIAL
CURRENT WITH INCREASING DOSES OF
IVACAFTOR AND WE CAN COMPARE
HUMAN AIRWAY CULTURES TO PIG
AIRWAY CULTURES AND WE FIND THAT
BOTH SPECIES RESPOND SIMILARLY.
SO WE THINK A SIMILAR DOSE FOR
PIGS WILL BE EFFECTIVE.
WE ALSO DID SOME OTHER STUDIES
WHERE WE GAVE ANIMALS DIFFERENT
DOSES OF IVACAFTOR AND TESTED
PLASMA LESMS TO MAKE LEVELS TO Y
WERE SIMILAR TO WHAT'S BEEN
REPORTED IN HUMAN.
SO WE BEGAN TO TREAT OUR G551D
PIG LET'S WITH IVACAFTOR IN
UTERO.
A NORMAL PIG PREGNANCY IS 114
DAYS SO WE BEGAN TO TREAT OUR
ANIMALS AT DAY 35.
THIS IS BEFORE MECONIUM IS
OBSERVED.
SO WE CONTINUED TREATMENT UNTIL
THE ANIMALS WERE BORN.
SO NOW WE HAVE OUR HETEROZYGOUS
SOWS RECEIVING THE IVACAFTOR,
G551D PIG LET'S EXPOSED IN UTERO
AND WE'RE ASKING IS THERE
CORRECTION.
SO THESE ARE SOME OF THE SAME
IMAGES WE LOOKED AT BEFORE FOR
THE PANCREAS.
THE WILD TYPE, THE G551D THAT
HAD AREAS OF DESTRUCTION, AND
NOW WHEN WE LOOK AT THE G551D
WITH FETAL IVACAFTOR TREATMENT,
WE SEE THE PHENOTYPE IS RESCUED.
WE FIND THE SAME THING IN THE
GALLBLADDER.
BEFORE WE HAD A GALLBLADDER
SEVERELY REDUCED IN SIZE, YOUR
THEY HAVE A MORE NORMAL
APPEARING GALLBLADDER.
WE ALSO LOOKED AT THE INTESTINE.
IT WAS OBVIOUS PRETTY EARLY ON
THAT THESE ANIMALS HAD A RESCUE
OF MECONIUM ILEUS.
THESE ANIMALS WERE ABLE TO PASS
MECONIUM AND WERE ABLE TO
SURVIVE FOR A LATER STUDY.
SO A REALLY IMPORTANT QUESTION
NOW IS THAT NOW THAT THE CF
PHENOTYPE HAS BEEN RESCUED IN
UTERO, IF WE WITHDRAW IVACAFTOR,
WILL THESE PIGS GO ON TO DEVELOP
AIRWAY DISEASE WITH TIME?
SO WE'VE HAD THE OPPORTUNITY TO
DO THIS A FEW TIMES.
SO THIS IS PRELIMINARY EVIDENCE.
THESE ARE HISTOLOGICAL IMAMONGS
IMAGESFROM THE LUNG, THE WHITE S
THE AIRWAY LUMEN IN A WILD TYPE
ANIMAL, THIS IS THE EPITHELIA.
YOU CAN SEE IN A WILD TYPE
ANIMAL THE AREAS ARE
MUCOUS-FREE.
IN OUR G551D ANIMAL, YOU CAN SEE
MUCUS IS STARTING TO ACCUMULATE
ON THE SURFACE AND WE HAVE THE
PRESENCE OF SCATTERED
NEUTROPHILS.
SO SOME BENEFITS AND LIMITATIONS
OF THE PIG.
FL CF PIGS HAVE DISEASE SIMILAR
TO HUMANS, IVACAFTOR TREATMENT
HAS PREVENTED THE CF PHENOTYPE
AND THESE PIGS CAN NOW BE RAISED
WITHOUT IVACAFTOR TO STUDY
DISEASE HOWEVER, LIKE HUMANS,
THE PRESENTATION, SEVERITY AND
TIMING TO PROGRESSION ARE
VARIABLE.
SO JUST TO FINISH UP, I'M GOING
TO COME BACK TO THE CHAT EPTION
THE CHALLENGESWE'RE FACING AND L
MODELS CAN HELP US OVER COME
THEM.
UNDERSTANDING MECHANISM OFS OF
OFPERSISTENT INFECTION,
INFLAMMATION AND REMODELING TO
DEVELOP NEW TREATMENTS.
REPEATED HIGH RESOLUTION CT,
MUCOCILIARY THERAPY IN LARGE AND
SMALL AIRWAYS, WE CAN DO
REPEATED BAL, AND WE CAN DO
REPEATED LUNG TISSUE SAMPLES AND
CONTROLLED NECROPSY AND
HISTOPATHOLOGY.
SO THESE ASSAYS CAN HELP US
DEVELOP NEW TREATMENTS.
ANIMAL MODELS CAN ALSO HELP US
TEST NEW MODULATORS OR CURRENT
MODULATORS PLUS ADDITIONAL
THERAPIES LIKE
ANTI-INFLAMMATORIES,
ANTIBIOTICS, AND FUNGALS, AND
THEY CAN ALSO HELP US DEVELOP
NEW THERAPIES THAT COULD IMPROVE
HOST DEFENSE DEFECTS.
AND THEN THE LAST THING HERE IS
JUST HOW CAN ANIMAL MODELS HELP
US WITH DISEASE PREVENTION FOR
THOSE WHO AREN'T ELIGIBLE FOR
MODULATORS.
THEY CAN HELP US ANSWER THE
QUESTION, WHERE IS THE
APPROPRIATE TARGET?
SHOULD IT BE LARGE AIRWAYS,
SUBMUCOSAL GLANDS, SMALL
AIRWAYS, OR ALL OF THESE?
ALSO IMPORTANT QUESTIONS ARE,
WHICH CELLS ARE THE MOST
IMPORTANT TO TARGET?
SHOULD IT BE SECRETORY CELLS OR
OTHER TYPES, IT CAN HELP US TEST
NEW THERAPEUTIC APPROACHES AND
ALSO TEST DIFFERENT DELIVERY
STRATEGIES.
AND THE G551D PIG COULD HELP US
WITH THE QUESTIONS SURROUNDING
EARLY MODULATOR TREATMENT, BUT I
THINK AS PROBLEMS DEVELOP IN
PEOPLE AND MODULATORS, THESE
ANIMAL MODELS MAY AID IN THE
DISCOVERY OF MECHANISMS AND
OTHER THERAPY PEW THERAPEUTIC T.
SO JUST -- THIS IS THE VERY LAST
SLIDE, THE EXAMPLE OF THAT WE'VE
USED IS LUNG FUNCTION BUT CF IS
A MULTISYSTEM DISEASE, SO THE
ANIMAL MODELS AND THE THINGS
THAT WE DISCOVER USING THE
ANIMAL MODELS CAN HELP US
TRANSLATE TREATMENTS TO OTHER
ORGANS, LIKE EXOCRINE AND
ENDOCRINE PANCREATIC DISEASE,
HEPATOBILIARY DISEASE, AND
INTESTINAL DISEASE.
AND THAT'S IT.
I'M A MEMBER OF THE UNIVERSITY
OF IOWA CF RESEARCH GROUP AND
THIS WORK IS -- A LOT OF PEOPLE
HAVE CONTRIBUTED TO THIS WORK.
SO THANK YOU.
>> THANK YOU, SARAH.
THAT WAS A GREAT TALK.
WITH THAT, I'D LIKE TO INTRODUCE
THE FINAL SPEAKERS FOR THIS
SESSION.
THE LAST TALK WILL BE GIVEN BY
DR. IRINA POLEJAEVA, PROFESSOR
OF DEVELOPMENTAL BIOLOGY AT UTAH
STATE UNIVERSITY AND ANN HARRIS,
PROFESSOR AND VICE CHAIR FOR
RESEARCH AT CASE WESTERN
RESERVE.
>> DO YOU SEE MY SLIDES?
>> WE SEE YOUR SLIDES, IRINA,
BUT NOT YOU.
>> THE SLIDES ARE ALSO NOT IN
PRESENTATION MODE.
>> THAT'S WHAT I'M TRYING TO
SWITCH.
ALL RIGHT.
THANK YOU FOR THE INTRODUCTION,
AND I ALSO WOULD LIKE TO THANK
THE ORGANIZING COMMITTEE FOR
INVITATION TO PRESENT.
THE SHEEP MODEL IS ONE OF THE
RECENT -- MOST RECENT MODEL
DEVELOPED IN THE FIELD, AND IT'S
A COLLABORATIVE PROJECT BETWEEN
UTAH STATE AND CASE WESTERN
RESERVE UNIVERSITY.
SO THE MODEL ACTUALLY WAS
INSPIRED BY WORK -- ANN HARRIS'
WORK, AND THE QUESTION THAT WE
ALWAYS -- WE OFTEN HEAR IS WHY
DO WE DEVELOP NEW MODELS AND I
CANNOT FOR SOME REASON ADVANCE
MY SLIDES.
>> I SEE AN ARROW ON THE BOTTOM
LEFT.
>> THANK YOU.
SO WHY ARE WE DEVELOPING A NEW
CF MODEL AND THE ANSWER WAS
SPECIFICALLY SHEEP IS QUITE
OBVIOUS, SO THE SHEEP HAS BEEN
USED AS ONE OF THE PRIMARY
MODELS TO STUDY HUMAN LUNG
DEVELOPMENT DUE TO A LOT OF
SIMILARITY IN PHYSIOLOGY AND
ACTUALLY JOHN GAVE AN EXCELLENT
OVERVIEW SLIDE ABOUT LARGE
ANIMAL MODELS AND THEIR
SIMILARITY TO HUMAN.
SO IN FACT, MUCH OF OUR
KNOWLEDGE IN HUMAN LUNG
DEVELOPMENT IS BASED ON THE SEMI
SEMINAL STUDIES ON SHEEP.
THE UNIQUENESS OF SHEEP IS
ALLOWING US TO MONITOR
DEVELOPMENT IN CLOSE CONDITIONS
OR CLOSER PREGNANCY LENGTH TO
HUMANS, SO SHEEP HAS NEARLY FIVE
MONTHS OF GESTATION COMPARED TO
LESS THAN FOUR MONTHS IN PIGS,
AND THEY ALSO HAVE SIMILAR
NUMBER OF OFFSPRING.
IT'S TYPICALLY ONE OR TWO LAMBS.
RARELY THREE, DEPENDING ON THE
BREED, WHICH MIGHT BE BENEFICIAL
TO TESTING PRENATAL THERAPEUTIC
INTERVENTION AND INDIVIDUAL
FETAL MONITORING.
SO ONE OF THE FIRST MODELS WE
DEVELOPED USED IN CRISPR/CAS
MEDIATED APPROACH TO SHEEP
FIBROBLAST IN VITRO, COMMONLY
USED FOR GENETIC MODIFICATIONS
IN COMBINATION WITH SOMATIC CELL
NUCLEOTRANSFER.
THE INITIAL MODEL WE DEVELOPED
WAS SIMPLE INTRODUCTION OF -- IN
EITHER IN EXON 2 OR EXON 11.
SO WE DESIGN GUIDE RNA TARGETING
TO DIFFERENT AXONS AND
TRANSVECTED FIBROBLAST CELL
FOLLOWED BY POPULATION OF THE
CELLS AND -- CELLS THAT HAVE
DESIRED GENOTYPE, SPECIFICALLY
WE'RE LOOKING FOR -- TO
FUNCTIONAL KNOCKOUT IN -- AND WE
USE THESE CELLS FOR FUTURE SCNT
WORK.
SO BASICALLY CELLS WERE
CONFIRMED BY -- ASSAYS AND A
SEQUENCE CONFIRMATION FOR THE
PRESENCE OF THESE.
FOR CLONING WE USE -- OOCYTES
WHICH WE ENUCLEATE OR USE IN
REMOVAL OF -- FACEPLATE FROM
THESE OOCYTES BY ASPIRATIONAL
DNA MATERIAL AND INTRODUCE
GENETICALLY MODIFIED CELLS, NULL
CELLS INTO -- OOCYTES THAT -- BY
FUSION, THESE TRANSFER INTO
ESTRUS SYNCHRONIZED RECIPIENTS
WHICH WOULD CARRY PREGNANCIES TO
TERM, AFTER ABOUT FIVE MONTHS OF
GESTATION, WE PRODUCED THE CFTR
NULL LAMBS.
SO INITIALLY WE PRODUCED A SET
OF TWO DIFFERENT TYPE OF ANIMALS
WITH CFTR NULL MUTATION IN THE
EXON 2 OR 11.
AND WE ALSO PRODUCED NOT ONLY
ANIMALS WITH -- KNOCKOUTS BUT
ALSO HETEROZYGOUS ANIMALS FOR
FUTURE LINE EN EXPANSION.
SINCE THEN WE HAVE 5508DEL AND
G542X, WE ALSO DESIGN THE
TEMPLATE TOGETHER WITH THAT
COCKTAIL OF RNP THAT WILL ALLOW
US TO INTRODUCE SPECIFIC
MUTATIONS AND TO USE THAT AS A
TEMPLATE FOR --.
SO CURRENTLY WE HAVE ABILITY TO
PRODUCE THESE DIFFERENT FOUR
TYPE OF CLONE ANIMALS, AND ALSO
HAVE FETAL FIBROBLAST CELLS THAT
COULD BE PROVIDED FOR IF YOU
DESIRE TO GENERATE PREGNANCY
USING THESE FETAL FIBROBLAST
CELLS.
WE ALSO HAVE HETEROZYGOUS
ANIMALS THAT CAN BE USED FOR --
TO GENERATE HOMOZYGOUS ANIMALS
WITH CF GENOTYPE.
JUST A QUICK REVIEW OF PATHOLOGY
COLLABORATIONS THAT WERE DONE ON
THE ANIMALS AND WHAT WE
CURRENTLY OBSERVE.
SO IT'S VERY SIMILAR TO JUST
DESCRIBED BY PREVIOUS SPEAKER,
WE SEE MECONIUM ILEUS IN 100% OF
CF ANIMALS, WHICH IS WILD TYPE
ON THE LEFT PANEL, AND YOU SEE
IN B AND D PANELS, CF MECONIUM
ILEUS.
THE ARROW POINTING HERE SHOWING
THE ACCUMULATION OF MECONIUM IN
SMALL INTESTINE AND HISTOLOGICAL
OBSERVATION HERE SHOWN IN
DILATED SMALL INTESTINE.
IMAGES OF COLON SHOWN HERE WILL
OBSERVE SIMILAR HOW IT WAS SHOWN
IN PIG'S MICRO COLON AND ALSO
VERY CLEAR CHANGES IN COLONIC
GLANDS FILLED AND DISTENDED WITH
LARGE AMOUNT OF MUCUS.
AGAIN SIMILAR TO PIGS, WE
CEELITIONS IN THE PANCREAS ON
THE BOTTOM PANEL, THE TWO IMAGES
ON THE LEFT SHOW WILD TYPE
PANCREAS AND THEN
DIFFERENT DEGREE OF FIBROTIC
CHANGES.
THE MIDDLE IS MORE MODERATE
CHANGES WITH SOME -- WHERE WE
CAN SEE THAT INCREASE IN SPACE
BETWEEN PANCREATIC -- AND ON THE
RIGHT BOTTOM PANEL WE SEE MUCH
MORE SEVERE GU FIBROTIC CHANGESN
THE PANCREAS.
WAS ALSO OBSERVED IN CF LAMBS.
SHOWN ON THE TOP HERE, NORMAL
WILD TYPE, LIVER, AND
VARIOUS DEGREE OF CHANGES WITH
BILIARY FIBROSIS IN THE LIVER OF
THE CF LAMBS AND SEVERE
INTRAHEPATIC CHOLESTASIS
APPEARS.
SO SUMMARIZING THE OBSERVATION
IN -- USING OUR
HISTOPATHOLOGICAL ASSESSMENT, I
ALREADY MENTIONED THE CHANGES IN
INTESS TIRNINTESTINE, PANCREAS ,
ALSO OBSERVED SIMILARLY TO PIGS,
MODEL HYPOPLASIA IN GALLBLADDER
AND WE ALSO OBSERVE THE ABSENCE
OF VAS DEFERENS IN THE CF MALES.
NO LESIONS AT BIRTH WERE
OBSERVED IN CF LAMB, AND WE ALSO
FREQUENTLY SEE HYDRONEPHROSIS,
WHICH IS RELATED TO COLON BUT
IT'S NOT A CF PHENOTYPE.
SO WITH THAT, I WILL PASS THE
MIC TO ANN.
ARE YOU READY, ANN?
>> YES, I'M HERE.
DO YOU SEE MY SCREEN?
>> YES, LOOKS GOOD.
>> THANK YOU VERY MUCH.
HOKAY.
SO I'M GOING TO DRILL DOWN A
LITTLE BIT MORE DETAIL ON SHEEP
CFTR AND THE USE THAT WE'RE
PUTTING THE CF SHEEP MODEL TO
ADVANCE UNDERSTANDING REALLY OF
HUMAN EARLY LUNG DISEASE, AND
OTHER ORGANS PRENATALLY WITH A
HOPE THIS WILL BE USEFUL GOING
FORWARD FOR HEMT.
SO JUST TO TELL YOU THAT THE
SHEEP CFTR PROTEIN IS REMARKABLY
SIMILAR TO THE HUMAN CFTR
PROTEIN, THESE ARE EXPERIMENTS
THAT WERE DONE BY CALVIN WHEN HE
WAS AT CASE SHOWING THE CONDUCT
CONDUCTANCE OF THE SHEEP CFTR
AND SHEEP TRACHEAL EPITHELIAL
CELLS, SHORT-CIRCUIT CURRENT
MEASUREMENTS.
WITH TIME, YOU CAN SEE THE RED
TRACES, THE CF SHEEP TRACHEAL
EPITHELIAL CELLS AND THE BLACK
DOTTED LINE THE WILD TYPE.
THESE ARE IN THE NULL ANIMALS
THAT IRINA SHOWED A MINUTE AGO.
FIRST BLOCKING SODIUM TRANSPORT
IN THE WILD TYPE WHEN YOU GET
FORSKALIN, YOU SEE AN ACTIVATION
OF THE CFTR CHANNEL, AND IN FACT
THAT'S INHIBITED NOT BY THE THE
INHIBITOR 172 BUT BY GLYH-101.
YOU CAN SEE DOWN HERE A SIMILAR
SHORT-CIRCUIT CURRENT TRACE FOR
HUMAN NASAL EPITHELIAL CELLS.
THE SHEEP CFTR CHANNEL ITSELF IS
A SLIGHTLY MORE ACTIVE CFTR
CHANNEL THAN THE HUMAN CHANNEL
BUT ESSENTIALLY THE MUTATIONS IN
THE HUMAN PROTEIN HAVE A SIMILAR
EFFECT ON THE SHEEP PROTEIN.
SO OUR INTEREST IN USING THIS
MODEL TO STUDY EARLY DISEASE,
EARLY CF DISEASE, RELATES
PRIMARILY TO THE FACT THAT MANY
YEARS AGO, WE STUDIED CFTR
EXPRESSION IN UTERO IN SHEEP,
AND WE FOUND THAT THOUGH THERE
IS VERY LITTLE CFTR IN THE LUNG,
AND OF COURSE NOW WE KNOW MUCH
MORE ABOUT THE CELL TYPES AND
THE LUNG THAT DO EXPRESS CFTR,
IN UTERO IN MID GESTATION IN THE
SHEEP AND ACTUALLY IN HUMAN, YOU
SEE QUITE AN ABUNDANCE OF CFTR
MESSENGER RNA.
SO THE QUESTION IS IF IT'S
MAKING MESSENGER RNA, LIKELY
MAKING PROTEIN, WHAT IS DOING
DURING EARLY DEVELOPMENT?
SO WE'VE DONE A DEVELOPMENTAL
TIME COURSE WITH THE TEAM IN
UTAH HAVE SET THIS UP FOR US,
AND ESSENTIALLY WE'RE TAKING
TISSUES FROM ALL ORGANS IN THE
SHEEP AT TIME POINTS THROUGH
GESTATION, BOTH FROM WILD TYPE
SHEEP AND FROM CF NULL SHEEP,
AND ON THIS SLIDE I JUST SHOW
YOU IN BLUE BASICALLY THE
PHENOTYPES, PANCREAS, INTESTINE,
LUNG, LIVER AND THE MALE GENITAL
DUCT IN WILD TYPE ANIMALS IN
BLUE, AND THE CFs IN A BUFF
COLOR.
AND WHAT YOU CAN SEE IS THAT
ALREADY BY BETWEEN 80 AND 100
DAYS OF GESTATION, WE SEE EARLY
PAN KPANCREATIC DISEASE, AS WE T
NO VISIBLE LESIONS IN THE LUNG,
WE SEE THE EARLY GALLBLADDER
DISEASE BEING REPORTED IN THE
OTHER LARGE ANIMAL MODELS.
SO WHAT WE'RE DOING HERE IS
WE'RE TRYING TO DRILL DOWN AND
THOUGH WE SEE NO ANATOMICAL
DEFECTS OR PATHOLOGICAL
HISTOLOGICAL DEFECTS IN THE
EARLY GESTATIONAL STAGES, WE'RE
LOOKING AT MORE DETAIL BY
LOOKING AT TRANSCRIPTOMIC
CHANGES, SO CHANGES IN GENE
EXPRESSION, BOTH IN BULK TISSUE
AND I'LL SHOW YOU IN A MINUTE AT
THE SINGLE CELL LEVEL.
AND THIS ENABLES US TO ASK, ARE
THERE SPECIFIC PATHWAYS OR
SPECIFIC GENES THAT ARE EITHER
MISREGULATED OR ALTERED IN SOME
WAY WHEN YOU COMPARE SHEEP WITH
CF TO WILD TYPE SHEEP.
AND THIS JUST SHOWS YOU ON THE
LEFT SIDE, WE'RE COMPARING LUNG
TYPE, LUNG 120 DAYS VERSUS 100
DAYS GESTATION.
THIS IS THE TOP IS DISTAL LUNG,
THE BOTTOM ONE IS PROXIMAL LUNG,
AND THIS VOLCANIC PLOT SHOWS
DIFFERENTIALLY EXPRESSED GENES,
DOWN REGULATED HUNDRED DAYS OR
UPREGULATED VERSUS 100 AND WE
SEE SPECIFIC GENES IN THERE LIKE
AQUAPORIN 5 INVOLVED IN WATER
TRANSPORT IN THE DISTAL LUNG AND
DOWN HERE WE SEE UNUSUAL
APPEARANCE OF SOME OF THE
SURFACTANT PROTEINS THAT WE'RE
NOT EXPECTING TO SEE AT THAT
AGE.
WE CAN ALSO, FROM THESE DATA,
GET A FANTASTIC IDEA OF GENE
EXPRESSION PROFILES, IN OTHER
WORDS, TAKING ALL THE DATA, AND
USING A PROGRAM THAT POOLS THE
DATABASED ON GENE EXPRESSION
VALUES, SO GENE EXPRESSION WITH
TIME.
WE SEE OBVIOUSLY GROUPS OF GENES
THAT GO DOWN WITH GESTATION,
OTHERS THAT GO UP, AND IN SOME
CASES ONES THAT ARE MOST
INTERESTING ARE THE ONES THAT GO
UP AND DOWN.
SO THIS CLASS OF GENES ARE
HIGHER 80 DAYS LOWER TO 100 THEN
THEY GO UP 120 AND THEN THEY
FALL OFF.
SO WE CAN USE ADVANCED
BIOINFORMATIC PROTOCOLS TO STUDY
BOTH INDIVIDUAL GENES AND ALSO
THE FUNCTIONAL PATHWAYS THAT
THEY BELONG TO.
WE'RE ALSO DOING SINGLE CELL
ANALYSIS TO TRY AND FIND OUT
WHETHER -- WHAT CELL TYPES MAY
BE SHOWING DIFFERENCES EARLY ON
IN GESTATION IN THE CF SHEEP
LUNG AND IF THAT PANCREAS AS
WELL COMPARED TO THE WILD TYPE
SHEEP AT THE SAME AGE.
THESE ARE SOME OF OUR EARLY DATA
SHOWING VERY NICELY THAT WE CAN
NOT EASILY BUT WE CAN DO ROBUST
SINGLE CELL RNA SEQUENCING ON
THE SHEEP LUNG.
THIS IS JUST TWIN LUNGS FROM 120
DAY WILD TYPE SHEEP, WE SEE NICE
DONOR CONTRIBUTION TO ALL THE
CLUSTERS, AND WHEN WE LOOK AT
THE DIFFERENT CLUSTERS OF
INDIVIDUAL CELLS ON THIS U MAP
PLOT, WE CAN IDENTIFY MOST OF
THE CELL TYPES THAT WE WOULD BE
EXPECTING TO SEE IN A DEVELOPING
LUNG.
BUT THIS HAS NEVER BEEN DONE
BEFORE AT SUCH A LEVEL OF
RESOLUTION THAT WE CAN LOOK AT,
FOR EXAMPLE, WE COULD TAKE ANY
ONE OF THESE CLUSTERS AND
COMPARE GENE EXPRESSION IN CF
AND NON-CF ANIMALS AND LOOK AT
THE SINGLE CELL AND THE SINGLE
GENE LEVEL TO LOOK FOR CHANGES
THAT RELATE TO THE CF PHENOTYPE.
SO JUST THIS POINTS THIS OUT,
THIS JUST IS THE SAME PLOT AS I
SHOWED YOU ON THE PREVIOUS
SLIDE, THE SAME U MAP PLOTS
WHERE WE'RE JUST HIGHLIGHTING
THE EXPRESSION OF THE ONE, TWO,
THREE, FOUR DIFFERENT SURFACTANT
PROTEIN GENES AND YOU SEE THEY
DO HAVE A SLIGHTLY DIFFERENT
CELLULAR EXPRESSION PATTERN IN
THE ONE TIME POINT BUT THE
DIFFERENT CELL TYPES AT THAT
TIME POINT.
AND THIS IS SOMETHING WE CAN DO
FOR ANY OF THE GENES THAT WE'RE
INTERESTED IN.
WE ALSO HAVE ORGANOIDS FROM BOTH
THE PANCREAS AND THE LUNG, WHICH
WE'RE USING FOR FUNCTIONAL
STUDIES NOT ONLY FOR EYE ON ION
TRANSPORT BUT WE CAN MAKE
ORGANOIDS OF DIFFERENT LINEAGE
CELL TYPES TO ESSENTIALLY ASSAY
WHATEVER PATHWAYS WE FIND TO BE
DIFFERENTIALLY EXPRESSED IN THE
CF LUNG VERSUS THE WILD TYPE
LUNG.
SO THAT'S A QUICK RUNTHROUGH
SOME OF OUR INITIAL EXPERIMENTS,
INITIAL DATA, TO SUMMARIZE WHAT
I'VE SAID TO YOU, THE -- OR
IRINA AND I HAVE BOTH SAID THE
CF SHEEP HAS A SEVERE PHENOTYPE
THAT MIRRORS SEVERAL KEY ASPECTS
OF THE HUMAN PHENOTIE. AT BIRTH,
PANCREATIC DISEASE IS SIMILAR,
INTESTINAL AND LIVER DISEASE ARE
MORE SEVERE, MALE GENITAL DUCTS
ARE ALSO ABSENT.
IN PEOPLE WITH CF, THERE'S A
LACK OF GROSS LUNG PATHOLOGY AT
BIRTH.
OUR GOAL ARE TO INVESTIGATE THE
EARLY DEVELOPMENT OF CF DISEASE
IN THE KEY ORGAN SYSTEMS.
WE ARE ALSO TRYING TO RESTORE
WILD TYPE EXPRESSION IN THE
DIGESTIVE TRACT TO OVERCOME THE
PROFOUND MECONIUM ILEUS THAT
YOU'VE SEEN.
AND WE'D ALSO LIKE TO MAKE THE
CF SHEEP ACCESSIBLE MORE BROADLY
TO THE RESEARCH COMMUNITY.
AND AS PEOPLE PLAN FUTURE
EXPERIMENTS IN THE LIGHT OF THE
HEMT PROPOSALS, PLEASE THINK
ABOUT THE SHEEP BECAUSE IT
ACTUALLY CAN PROVIDE A RESOURCE
THAT -- ANOTHER LARGE ANIMAL
RESOURCE THAT CAN BE VERY
PROFOUNDLY IMPORTANT IN MAKING
ADVANCES.
MY LAST SLIDE IS JUST A -- IF I
CAN GET TO ADVANCE, MY LAST
SLIDE WAS THE SUMMARY OF
EVERYONE WHO'S BEEN INVOLVED.
THIS IS A PROJECT THAT'S BEEN
GOING ON FOR MANY YEARS BETWEEN
UNIVERSITY OF UTAH AND MOST
RECENTLY AT CASE WESTERN.
THANK YOU.
>> OKAY, THANK YOU, ANNE AND
IRINA.
THAT WAS A GREAT PRESENTATION ON
THE SHEEP MODEL.
SO JUMPING INTO THE Q & A
SESSION, WE HAVE OBVIOUSLY A
NUMBER OF QUESTIONS IN THE CHAT
SO WE THANK EVERYBODY FOR ASKING
THOSE.
SOME OF THE ANSWERS HAVE BEEN
DIRECTED BACK TO THE CHAT, SO
LOOK THERE IF YOU HAVE A
QUESTION THAT YOU DIDN'T HEAR AS
WE GO THROUGH THIS PANEL.
BUT THERE WERE A LOT OF
QUESTIONS THAT CAME THROUGH THE
CHAT THAT REALLY WERE TARGETED
TO ALL OF THE SPEAKERS, SO I
THINK WE'RE GOING TO START WITH
THOSE.
SO THE FIRST QUESTION FOR ALL
THE SPEAKERS IS FOR THE USE OF
ETI COMPOUNDS OR HE MT COMPOUNDS
IN ANIMAL OR IN VITRO MODELS,
WHAT'S THE SOURCE OF THE
MOLECULES FOR YOUR STUDIES?
AND IS THIS EMERGING CONSENSUS
FOR SOURCING THE COMPOUNDS OR
DOSING AMOUNTS AND REGIMENS?
WHO WANTS TO START WITH THAT?
>> I CAN SAY FOR SOURCE, I'M NOT
GOING TO PROMOTE ONE COMPANY
OVER ANOTHER, BUT IF YOU PUT IN
THE VX NUMBERS INTO GOOGLE AND
SAY FOR SALE, YOU CAN FIND
SEVERAL COMPANIES WHO ARE
SELLING THEM.
I'VE CHOSEN NOT TO GO THROUGH
VERTEX BECAUSE I FEEL LIKE SOME
OF THE COMPANIES THAT YOU GET
THE DRUGS FOR OR FROM HAVE YOU
KIND OF JUMP THROUGH HOOPS WHEN
YOU HAVE TO PUBLISH OR GET
EVERYTHING APPROVED, SO THAT'S
JUST WHAT I'LL SAY ON THAT.
>> YES, I'VE ACTUALLY DONE IT IN
MORE OF A MIXED MODEL.
SOME OF THE COMPOUND I'VE USED
STRAIGHT FROM VERTEX AND THEY
ACTUALLY HELPED, FOR THE RAT
THEY HELPED ME WITH THE INITIAL
DOSING CHOICE FOR IVACAFTOR.
AND THEN SINCE THEN, I'VE DONE
THE SAME SORT OF STRATEGY AS
CRAIG WHERE I LOOKED FOR
COMPANIES THAT CAN MAKE THESE
CHEMICALS IN BULK.
JOHN?
>> YEAH, I MEAN, WE HAVE A
SOURCE WHERE WE GET IT IN BULK.
THERE ARE MULTIPLE PLACES WHERE
YOU CAN BUY IT.
>> I THINK THE DOSING IS A
BIGGER CHALLENGE.
I THINK WHEN I STARTED THE
EXPERIMENTS I ASKED VERTEX, WE
DID FIND SOME GOOD INFORMATION
IN THE PRODUCT INSERT.
IN TERMS OF THE LARGER ANIMALS,
SARAH, HOW HAVE YOU HANDLED THE
SOURCING AND DOSING FOR YOUR
MODELS?
>> SO WE ALSO PURCHASE OURS IN
BULK, JUST FREE AGENT GRADE AND
HAVE COLLABORATED WITH SOMEONE
TO COMPOUND IT FOR US, AND IN
CHOOSING A DOSE, WE'VE MEASURED
PLASMA LEVELS AND JUST TO
MAKE -- I MEAN, OUR FIRST
EXPERIMENTS WERE KIND OF A
GUESS, AND WE WERE LUCKY THAT
SOME OF THE FIRST THINGS THAT WE
TRIED WERE SUFFICIENT TO PROVIDE
CORRECTION.
>> I'D JUST ECHO THAT THE
FORMULATION IS PROBABLY THE MOST
DIFFICULT PART OF IT ALL.
I MEAN, YOU HAVE TO DO THE PK,
AND KNOW WHERE YOU'RE AT IF YOU
WANT TO USE IT IN AN ANIMAL.
>> AND FOR THE SHEEP, ARE THERE
ANY DOSING INTRICACIES THAT
SHOULD BE TAKEN INTO
CONSIDERATION?
>> WE HAVEN'T TAKEN ON MUCH OF
THAT AT THE MOMENT.
ALTHOUGH YOU KNOW I THINK THE
SHEEP -- THE LAMBS ARE ABOUT THE
SAME SIZE AS -- BOTH ARE ABOUT
THE SAME SIZE AS HUMANS ARE.
I'M GOING TO SLIGHTLY DEFLECT
THAT QUESTION BECAUSE I THINK
ONE OF THE ISSUES THAT WE'VE HAD
IS WANTING TO TRY AND HELP WITH
THE COMPANIES WHO'VE GOT MAYBE
OTHER DRUGS IN THEIR PIPELINE
THAT AREN'T SPECIFICALLY -- FOR
EXAMPLE, FOR G551D, BUT FOR
OTHER APPROACHES TO NEW
THERAPIES THAT I THINK THINGS
DON'T SEEM AS EASY AS ONE MIGHT
HOPE IN TERMS OF SETTING UP
COLLABORATIONS THAT MIGHT
ADVANCE THE SUBJECT.
>> I THINK I SEE SOME ADDITIONAL
QUESTIONS ABOUT THE SPECIFIC
SOURCE IN THE CHAT.
I THINK TO AVOID MAYBE PROMOTING
ONE COMPANY OVER THE OTHER, IF
ANYBODY WANTS TO EMAIL ME OR
JOHN OR ANYONE ON THE PANEL TO
SEE EXACTLY WHERE WE'RE GETTING
AT, WE'D BE HAPPY TO SHARE
PRODUCT INFORMATION.
MOVING ON TO THE SECOND QUESTION
THEN, THIS IS ALSO FOR
EVERYBODY.
IS THERE CONSENSUS REGARDING THE
HIGHLY EFFECTIVE MODULATOR
THERAPY ON INFLAMMATORY
RESPONSES IN THE LUNG AND OTHER
ORGANS CROSSING IN VITRO AND IN
VIVO MODELS AND RELATING THAT
BACK TO THE PATIENTS?
ANYBODY WANT TO TAKE THIS ONE?
>> THAT'S A COMPLICATED ONE.
SO REPEAT PART OF THE QUESTION.
SO IT'S EVALUATING THE STATUS OF
INFLAMMATION TO START AND THE
RESPONSE OF THE HIGHLY EFFECTIVE
MODULATOR, IS THAT CORRECT?
>> RIGHT.
>> YOU KNOW, I'D SAY IF YOU
CONSIDER INFLAMMATION IN THE
PANCREAS, WE FIND THAT FIRST
THREE MONTHS OF LIFE WHERE
ANIMALS ARE BEING WEANED AT TWO
MONTHS OF LIFE, THAT THERE'S A
CRITICAL WINDOW WHERE IT WILL
DETERMINE LONGER TERM IF THE
ANIMAL MAINTAINS PANCREATIC
SUFFICIENCY, BUT UNTIL THE
ANIMAL IS ALMOST FULLY GROWN,
THERE'S THIS UNDERLYING RESIDUAL
INFLAMMATION THAT'S NOT
CORRECTED BY -- AT LEAST IN ALL
ANIMALS BY THE MODULATORS.
I SEE IT AS UNTIL THE ANIMALS
ARE FULLY GROWN, THE STRESS ON
THE PANCREAS CAN BE GREAT.
I MEAN, ESPECIALLY AT WEANING.
AND SO IF YOU DON'T HAVE ENOUGH
CFTR, THE PIPES GET CLOGGED AND
THEN -- BUT IF THE ANIMAL GOES
PANCREATIC-INSUFFICIENT LATER IN
LIFE, THEY'RE LIKELY NOT GOING
TO COME BACK.
SO IF YOU TAKE AWAY THE
MODULATOR, YOU'LL GET
INFLAMMATION.
-- IT BACK, BUT THEY WON'T
RECOVER.
>> SO JOHN, CAN I JUST ASK IN
THAT CONTEXT WHETHER YOU'VE
LOOKED -- I'M SURE YOU HAVE
LOOKED VERY CAREFULLY TO CHECK,
BUT YOU SAID THE TUBES GET
BLOCKED, BUT YOU ARE SURE
THERE'S NO COMPONENT OF THE
TUBES NOT FORMING PROPERLY IN
THE FIRST PLACE?
>> WELL, WE TREAT -- 80% OF CF
FERRETS, REGARDLESS OF THE
GENOTYPE, HAVE MECONIUM ILEUS
AND THERE'S SOME GENETIC
COMPONENT THAT PROTECTS THE 20%
THAT DON'T.
SO ALL THE ANIMALS WE'RE
BIRTHING, JUST BECAUSE THE
LOSSES ARE SO GREAT AND THE COST
IS TO GREAT, ARE BORN ON SOME
COMBINATION OF MODULATORS AT
BIRTH.
SO THIRD TRIMESTER, THEY GO ON
AND IT LARGELY PREVENTS MECONIUM
ILEUS.
>> AND HOW ABOUT IN THE
PANCREAS?
BECAUSE I MEAN, THAT'S THE
SAME -- IN PART THAT'S THE SAME
QUESTION, IS THAT OTHER
PANCREATIC DUCTS GETTING
OBSTRUCTED OR ARE THEY NOT
FORMING PROPERLY?
>> WE DON'T SEE -- UNLIKE THE
PIG AND THE SHEEP, THE AMOUNT OF
INJURY IN THE PANCREAS AT BIRTH
IS PRETTY MINIMAL IN A CF
FERRET, KNOCKOUT OR OTHERWISE.
THERE IS SOME INCREASED
INFLAMMATION BUT THERE'S NOT A
LOT OF CELL LOSS.
IF YOU'RE NOT ON MODULATOR, THAT
PROGRESSES EXTREMELY QUICKLY,
FIRST MONTH OF LIFE, BUT TO
BECOME PANCREATIC-INSUFFICIENT
VERY RAPIDLY.
THAT'S A BIT DIFFERENT THAN
HUMAN, WHERE THERE'S SORT OF --
WE'LL WAX AND WANE, ABOVE OR
BELOW THAT 200 LEVEL OF FECAL
LASTASE THAT DEFINES PANCREATIC
INSUFFICIENCY.
SO WE DON'T SEE DEVELOPMENTAL
ABNORMALITIES IN THE PANCREAS.
>> INTERESTING.
THANK YOU.
>> THE VAS DEFERENS, YOU DO.
>> YES.
>> SUSAN, WHEN YOU'VE -- NEXT
QUESTION, CAN YOU GIVE US THE
TIME STAMP THAT'S ON THE CHAT
BECAUSE IT'S ACTUALLY QUITE HARD
TO FOLLOW WHERE YOU'RE WORKING
FROM.
>> SO ACTUALLY MARA HAS SENT ME
THE QUESTIONS.
>> I SEE.
THAT'S WHY I CAN'T SEE THEM.
THAT'S FINE.
>> THE QUESTIONS ARE BURIED IN
THE CHAT ABOVE.
BUT THEY ARE HARD TO FIND.
SO MOVING ON TO THE THIRD
QUESTION THEN, THIS IS, AGAIN,
FOR EVERYBODY.
GIVEN THE INCREASE IN IN UTERO
EXPOSURE HIGHLY EFFECTIVE
MODULATOR THERAPY, WHAT CAN THE
ANIMAL MODELS TELL US ABOUT
POTENTIAL NEGATIVE EFFECTS FROM
WITHDRAWAL FROM THE DRUG AT
BIRTH, BOTH FROM THE AFFECTED
AND NON-AFFECTED BABIES?
I THINK THIS WOULD BE DIRECTED
TOWARDS THE PIG AND FERRET
EXPERIMENTS PRIMARILY.
>> I'LL TAKE IT FIRST.
HETEROZYGOUS ANIMALS AREN'T
AFFECTED IN UTERO AFTER BIRTH.
CF ANIMALS BORN ON MODULATORS DO
VERY POORLY IF THE MODULATOR IS
REMOVED AT BIRTH.
THERE'S LIKE ZERO SURVIVAL.
AND THAT'S DUE TO A LOT OF
DIFFERENT THINGS, BUT MOSTLY THE
GUT, ONSET OF GUT OBSTRUCTION.
SO AN ANIMAL BORN OFF MODULATOR
AND REARED IS EASIER TO REAR
THAN ONE THAT'S BORN ON
MODULATOR AND TAKEN OFF THE
MODULATOR AT BIRTH, PROVIDED
THAT AGAIN WE LOSE 80% IF YOU'RE
BORN OFF MODULATOR TO MECONIUM
ILEUS, SO IT'S THAT SELECT 20%
THAT WILL BE EASIER TO REAR THAN
AN ANIMAL COMING OFF MODULATOR.
>> SO IN THE PIGS, I THINK THE
WILD TYPE AND HETEROZYGOUS
ANIMALS HAVEN'T -- IT DOESN'T
MATTER WHEN THEY COME OFF OF
MODULATORS AT BIRTH.
FOR THE CF ANIMALS, ONE OF THE
THINGS THAT WE NOTICE IS A
DIFFERENCE IN WEIGHT GAIN.
I THINK THAT'S PRETTY OBVIOUS
WITHIN THE FIRST WEEK.
OTHER THINGS ARE A LITTLE BIT
MORE VARIABLE.
SO I WOULD SAY THE WEIGHT GAIN
IS THE THING WE NOTICE FIRST.
>> I'D ALSO COMMENT THAT IF WE
TAKE AN ANIMAL OFF MODULATOR,
THEY'RE GOING ON PANCREATIC
ENZYMES.
WE'RE DOING EVERYTHING TO
PREVENT -- AND LAXATIVES, TO
PREVENT GUT AND IMPROVE WEIGHT
GAIN.
>> HAVE YOU DONE ANY MOUSE IN
UTERO EXPOSURES LIKE THIS?
>> WE'VE STARTED DOING THAT WITH
THE HUMANIZED AND SIMILAR TO
JOHN AND SARAH, WE HAVEN'T
REALLY SEEN ANY DIFFERENCES WHEN
IT COMES TO TAKING THEM OFF
MODULATORS ONCE THEY'RE BORN.
BUT THEN AGAIN, WE HAVEN'T
LOOKED AT SOME OF THE THINGS
THAT AT LEAST I'VE SEEN ONE
POSTER ON MAYBE ISSUES WITH LUNG
DEVELOPMENT WITH IN UTERO,
WHETHER IT'S NON-CF, I GUESS,
MICE.
WE HAVEN'T LOOKED AT THAT SO.
BUT AS FAR AS THEM LIVING,
THEY'RE JUST FINE OFF THE
MODULATORS.
THE CF MICE, ONCE YOU TAKE THEM
OFF, THE MODULATORS, IF YOU TAKE
THEM OFF EARLY ENOUGH, YEAH,
THEY'LL OBSTRUCT AND HAVE
REDUCED GROWTH.
>> GREAT.
SO THIS QUESTION ACTUALLY LEADS
VERY WELL INTO THE NEXT
QUESTION, WHICH AGAIN IS FOR
EVERYBODY.
AS DISCUSSED IN MULTIPLE
PRESENTATION, SOME ANIMAL MODELS
SHOW A MUCH HIGHER FREQUENCY OF
MECONIUM ILEUS OR SEVERITY OF
THE GI SYMPTOMS THAN THE HUMANS
MAY EXPERIENCE.
ARE THERE KNOWN FACTORS THAT
MITIGATE INTESTINAL PHENOTYPE IN
HUMAN RELATIVE TO THESE OTHER
MODELS?
>> WE KNOW IN MICE, ONCE YOU
START HAVING THEM NOT ON
GENETICALLY DISTINCT BACKGROUND,
THEY'LL ACTUALLY DO BETTER.
IN MICE, YOU WON'T HAVE AS MUCH
OBSTRUCTION ON WHAT WE CALL A
MIXED BACKGROUND, AND THAT'S
WHAT I WOULD SAY HUMANS ARE.
SO THAT WOULD BE MY ANSWER.
>> THERE ARE KNOWN GENETIC
FACTORS.
GAIR FACTORS, THAT IMPACT MECONM
ILEUS.
I THINK IN THE FERRET, WE KNOW
THESE GENETIC FACTORS OR
MODIFIER GENES EXIST.
WE'VE SEEN KNOCKOUT FERRETS,
VERY FEW BUT CFTR KNOCKOUT THAT
ARE PANCREATIC SUFFICIENT BUT
GET LUNG DISEASE JUST AS AN
EXAMPLE.
THERE ARE HERITABLE TRAITS IN
THE MECONIUM ILEUS THAT AFFECTS
PREDISPOSITION IN UTERO TO THAT
IN FERRETS.
SO IT'S JUST VERY DIFFICULT TO
TRACK DOWN THESE GENES FROM A
COST STANDPOINT, THE BREEDING, I
THINK YOU CAN ONLY DO THAT IN
MICE.
>> I AGREE THAT -- I'VE SORT OF
TRIED TO GO DOWN THAT PATH FOR
THE RAT TO FIGURE OUT IF I CAN
NUDGE THE INTESTINAL DISEASE TO
BE A LITTLE BIT MORE FAVORABLE,
AND IT'S A REALLY DIFFICULT
TOPIC.
>> JUST TO POINT OUT THAT IT'S
NOT JUST A STRAIGHTFORWARD
MECONIUM ILEUS, AT LEAST IN THE
SHEEP AND I THINK ALSO IN THE
PIG.
THERE'S ACTUALLY THIS MICRO
COLON PHENOMENON AND THE
OBSTRUCTION IS REALLY VERY HIGH
UP IN THE INTESTINE.
AND SO THERE MAY BE LOCAL
EFFECTS ON THE ACTUAL -- THE
BORDER BETWEEN THE SMALL
INTESTINE AND THE COLON, AND
THERE MAY BE DIFFERENT
DIFFERENCES THERE THAT MAY BE
CONTRIBUTING TO IT.
>> WHAT I'VE SEEN ACTUALLY IN
THE RAT IS THAT WE -- THE RAT
HAS LESS MECONIUM ILEUS OR SORT
OF INTESTINAL PROBLEMS AT BIRTH
LIKE SOME OF THE OTHER SPEE, BUT
THE INCIDENCE OF MORE OF A D IOS
SYNDROME LATER IN LIFE,
INTESTINAL OBSTRUCTIVE SYMPTOM
IS REALLY PERVASIVE.
A LOT OF THE ANIMALS THAT HAVE
SEVERE LUNG DISEASE ACTUALLY
HAVE WORSENED GI EFFECTS SOON
AFTER.
SO IT DOES SEEM LIKE THERE'S
SOME INTERACTION BETWEEN THE
WHOLE BODY PHYSIOLOGY AND THE
HEALTH OF THE INTESTINE AS WELL.
ALL RIGHT.
SO MOVING ON TO QUESTION FIVE,
FOR THE ANIMAL MODELS THAT HAVE
BENEFITED FROM OR REQUIRED
ANTIBIOTIC SUPPRESSION TO
IMPROVE SURVIVAL, HAS THE EARLY
USE OF HIGHLY EFFECTIVE
MODULATORS AFFECTED THE NEEDS
FOR THE ANTIBIOTICS OR THE
MICROBIOLOGY OF THE LUNG AT TIME
OF SACRIFICE?
>> I CAN MAKE A COMMENT ON THAT.
YOU KNOW, EARLY ON WHEN WE'VE
BEEN REARING CFTR KNOCKOUT
FERRET, WE HAD TO KEEP THEM ON
ANTIBIOTICS OR THEY WOULD GET
LUNG INFECTIONS AND DIE VERY
RAPIDLY.
MOST OF THEM WERE ENTERIC
BACTERIA, ENDOGENOUS TO FERRETS.
MORE RECENTLY, AS WE HAVE BEEN
REARING ANIMALS ON HIGHLY
EFFECTIVE MODULATORS AND TAKING
THEM OFF THREE MONTHS OF AGE TO
DEVELOP LUNG DISEASE, WHEN WE
FIND TO DEVELOP THE CHRONIC
DISEASE STATE AND LIKELY WITH
PSEUDOMONAS AS I SHOWED WITH
MUCOID CONVERSION, YOU NEED TO
RESCUE THEM EARLY IN LIFE.
AND WE RESCUE WITH MODULATORS AT
LEAST AT FIRST RATHER THAN
ANTIBIOTICS, BUT I THINK THAT
PROCESS THAT IS -- THAT OCCURS
IN HUMANS ALL THE TIME IS WHAT
EVOLVES THAT CHRONIC DISEASE
STATE WITH BACTERIA THAT DON'T
KILL THE HOST AS RAPIDLY AS WE
HAD SEEN WITH EARLY LUNG DISEASE
IN CFTR KNOCKOUT FERRETS.
>> HAVE ANY OF THE OTHER MODELS
USED ANTIBIOTICS IN THIS SIMILAR
WAY?
THIS LEADS ON TO WHAT WILL
LIKELY BE THE LAST QUESTION AS
WE ONLY HAVE 3 MINUTES LEFT.
THE QUESTION IS THAT IT'S A
MAJOR ADVANCE THAT SEVERAL CF
ANIMAL MODELS DEVELOP -- DO ANY
DEVELOP TRUE CHRONIC INFECTION
WITH THE SINGLE PERSISTENT
LINEAGES OF BA BACTERIA THAT
PRODUCE WAXING AND WANING
MANIFESTATIONS LIKE SEEN IN
HUMANS?
>> THE ANSWER WOULD BE NO, WE
HAVE TO EXOGENOUSLY PUT IN THE
BACTERIA TO GET THEM HAVE ANY
KIND OF INFLAMMATORY RESPONSE OR
LUNG DISEASE.
>> I THINK WHAT'S INTERESTING
WHAT WE'VE SEEN WITH THE RATS,
WHEN WE PUT THE BACTERIA IN,
MOST OF THE RATS THAT LIVE PAST
FOUR TO SIX WEEKS OF AGE HAVE
PRETTY CLEAN LUNGS BUT WHEN WE
DO PUT THE BACTERIA IN, IT
LARGELY STAYS THERE.
NOW WE'VE GOTTEN DETECTABLE AT
DAY 56 AFTER INFECTION.
BUP WHAT'S INTERESTING, AND IT
COULD BE JUST A FACTOR OF THE
MODEL ITSELF, WE DON'T SEE A LOT
OF WORSENING OF THE OVERALL
ANIMAL CONDITION.
SO WE DON'T -- WE SEE AN INITIAL
WEIGHT DROP.
OF THE ONES THAT STAY INFECTED,
YOU KNOW, THEY NEVER QUITE
RECOVER BACK TO THEIR UNINFECTED
LITTER MATE OR COUNTERPARTS, BUT
WE DON'T REALLY SEE LIKE A SLOW
DECLINE.
THEY GET THE BACTERIA IN THEIR
LUNGS AND THEY SORT OF COPE WITH
IT.
THEY SORT OF LIVE WITH IT.
I THINK WHAT'S INTERESTING ABOUT
THE QUESTION THE WAY IT'S POSED
IS THAT A LOT OF -- THE HUMAN
LUNG DISEASE MAY BE AFFECTED
POSITIVELY OR OTHERWISE BY THE
ANTIBIOTIC REGIMENS THAT THESE
PATIENTS ARE GOING ON AND COMING
OFF OF, AND SO ONE OF THE THINGS
THAT I AM INTERESTED IN MODELING
IN THE RATS IS RECAPITULATING
SOME OF THOSE ANTIBIOTIC
EXPOSURES TO ASK DO THE RATS
IMPROVE DURING ANTIBIOTIC
TREATMENTS OR WORSEN ONCE THEY
COME OFF, AND THAT KIND OF
THING.
>> IN THE FERRET, THEY GET
CHRONICALLY DISEASED.
I THINK THE NARROWING OF
PARDEEP'S QUESTION ABOUT IS
THERE CLONAL EXPANSION, WE CAN'T
SAY THAT FOR SURE, BUT THE
NARROWING OF THE TYPES OF
BACTERIA THAT ARE IN THE LUNG
TAKES QUITE A WHILE.
THE ONE I SHOWED WITH THE MUCOID
PSEUDOMONAS WHERE IT WAS PREDOM
NAPTLY ALL THE SAME MUTATION, WE
DON'T KNOW IF IT WAS CLONAL IN
THAT PARTICULAR CASE, BUT SAME
MUTATION WITHIN THE PSEUDOMONAS
GENOME THAT LED TO THE MUCOID
PHENOTYPE, THAT WAS 95% OF ALL
THE BACTERIA IN THE LUNG.
NOW THERE WERE OTHER BACTERIA IN
THE FLUID LINING THAT -- IT WAS
IN THE BOWEL, BUT THE
PSEUDOMONAS IS IN THE LUNG.
>> ALL RIGHT.
IT LOOKS LIKE WE'RE AT TIME.
THANK YOU ALL TO THE SESSION ONE
SPEAKERS.
WELCOME TO SESSION 2.
IN THIS SESSION WE'LL TAKE YOU
THROUGH A SPECTRUM OF CLINICAL
AND TRANSLATIONAL RESEARCH ON CF
LUNG DISEASE PATHOPHYSIOLOGY AND
PROCESSES INCLUDING STRUCTURAL
CHANGES WITH CHRONIC INFECTION
AND CROSS-TALK WITH ENDOCRINE
SYSTEMS AND NUTRITION AND
METABOLISM, THE GOAL TO DEFINE
CLINICAL CHALLENGES FOR CF
PATIENTS ON HIGHLY EFFECTIVE.
I'LL BE MODERATING WITH OUR
WORKSHOP CO-CHAIR DR. KATHERINE
HISERT, SCIENTIST AT NATIONAL
JEWISH HEALTH.
SO I'LL INTRODUCE THE SPEAKERS
AND THEY WILL PRESENT BACK TO
BACK AS THE FIRST SESSION AND
WE'LL DO THE Q&A AFTER EVERYONE
HAS PRESENTED.
WE'LL START THE SESSION WITH DR.
FRANK McKEON, UNIVERSITY OF
HOUSTON, WITH DR. WA XIAN, ALSO
ASSOCIATE PROFESSOR AT STEM CELL
CENTER AND THEY WILL COVER
PATHOGENIC STEM CELL VARIANTS.
NEXT DR. ESZTER VLADAR,
ASSISTANT PROFESSOR IN
MEDICINE-PULMONARY SCIENCE,
UNIVERSITY OF COLORADO ANSCHUTZ
MEDICAL CAMPUS, COVERING
EPITHELIAL AND FUNCTIONAL
RESPONSES OF HIGHLY EFFECTIVE
MODULATOR THERAPY.
DR. PRADEEP SINGH AND DR. ANDREA
KELLY.
AND I'LL END WITH CURRENT
NUTRITIONAL CHALLENGES AND GAPS
IN CF IN THIS POST-MODULATOR
WORLD.
WITH THAT I WILL LET DR.
McKEON TAKE OVER.
>> THANK YOU VERY MUCH.
TODAY I'M GOING TO TALK ABOUT
NEW WORK IN THE LABORATORY.
NONE IS PUBLISHED.
GOD WILLING, IT WILL BE, FOCUSED
ON ADVANCED POTENTIALLY
MODULATOR RESISTANT DISEASE.
SO, THE POINTS I WANT TO COVER
TODAY ARE SINGLE CELL CLONING
TECHNOLOGY ADAPTED TO CYSTIC
CYSTIC FIBROSIS LUNGS, ALL FROM
THE UNIVERSITY OF IOWA, FROM THE
TRANSPLANT CENTER THERE, BY
DEFINITION THEY ARE ADVANCED
STAGE CYSTIC FIBROSIS LUNGS, AND
THIS MAY ADDRESS SOME OF THE
ISSUES RAISED IN THAT STUNNING
TALK BY MELANIE LAWRENCE.
BUT JUST TO SUMMARIZE ALL OF
THIS, I'M GOING TO PRESENT,
CYSTIC FIBROSIS IS DOMINANT BY
FIVE PATHOGENIC VARIANTS, STEM
CELL VARIANTS WHICH IN AGGREGATE
RECAPITULATE THE CYSTIC FIBROSIS
LUNG PATHOLOGY.
BREAKING IT DOWN FURTHER INTO
SINGLE TYPES, THERE ARE THREE
PRO-INFLAMMATORY VARIANTS, TWO
PRO FIBROTIC, TWO THAT ARE
CONSTITUATIVELY PRODUCING MUCIN.
THREE OF THOSE VARIANTS ARE
COMING TO THOSE THAT WE'VE SEEN
IN COPD, AND TWO ARE NOVEL
PRO-INFLAMMATORY VARIANTS WE'VE
ONLY FAR SEEN IN CYSTIC
FIBROSIS.
SHOULD NOTE THE PATHOGENIC
FEATURES OF THEY CELLS ARE
UNAFFECTED BY CFTR GENE
COMPLEMENTATION OR CFTR
MODULATORS.
AND AT THE END I'LL TALK ABOUT
DRUG DISCOVERY FOR PARTICULARLY
TARGETING THESE PATHOGENIC
VARIANTS.
SO, PRETTY MUCH THIS IS A
SUMMARY OF HOW WE GENERATE CLONE
LIBRARIES, 1/1,000 OF THE
EPITHELIAL CELLS, THE CLONOGENIC
ONE OF ONES DEVELOPED IN THE
'70s BY HOWARD GREEN.
IN A STUNNING NOT A FORMAL
MENTORSHIP BUT ONE OF THESE
INTERESTING INFORMAL
MENTORSHIPS, WA XIAN AT THE BIG
HAM AND WOMEN'S - BRIGHAM AND
WOMEN'S AT THE TIME WANTED
INVESTIGATE HIGH GRADE OVARIAN
CANCER, NOW STEM CELL IN CHRONIC
INFLAMMATORY DISEASES.
YOU GENERATE LIBRARIES, IT'S A
POSITIVE SELECTION FOR
CLONOGENIC CELLS, DIFFERENTIATED
CELLS DON'T SHOW UP.
YOU'RE LOOKING AT JUST THE STEM
CELL COMPONENT.
BY A SINGLE CELL RNAseq
ANALYSIS THESE ARE FOUR CASE
CONTROLS FROM BOTH UNIVERSITY OF
CONNECTICUT AND HOUSTON
METHODIST HOSPITAL.
THESE WERE LUNG DONORS THAT
DIDN'T FIND RECIPIENTS.
THEY DON'T HAVE ANY OBVIOUS LUNG
DISEASE.
THEY HAVE SOME OF THESE
VARIANTS.
SO THESE VARIANTS ARE ALL
PREEXISTING, NOT ONLY IN CONTROL
CASES BUT THEY ARE PRESENT IN
MID-GESTATION, FETAL DEMISE
LUNG.
AND BUT NOW YOU LOOK AT A CYSTIC
FIBROSIS LUNG.
SO HERE IS THE NORMAL LUNG STEM
CELL, THIS BLUE ONE.
IN ALL THE NORMAL CASES IT'S THE
DOMINANT ONE.
IF YOU LOOK AT CYSTIC FIBROSIS
THE NORMAL GUYS ARE OVERWHELMED
BY THESE VARIANTS.
AND THESE ARE THE FOUR CYSTIC
FIBROSIS CASES THAT CAL PAREK
SENT OVER.
THESE VERY LITTLE IN THE WAY OF
NORMAL STEM CELLS ANYMORE IN
THESE.
IF YOU LOOK AT THESE WHOLE
LIBRARIES AS A SINGLE ENTITY,
XENOGRAFT INTO HIGHLY
IMMUNODEFICIENT MICE, THEY
SELF-ASSEMBLE INTO EPITHELIAL
CYSTS.
AND YOU CAN SEE THAT THE
EPITHELIA HERE IS PRETTY NORMAL.
THERE'S SOME CILIATED CELLS,
SOMEWHAT MUCIN-POSITIVE CELLS.
IF YOU DO THE SAME THING WITH
CYSTIC FIBROSIS LIBRARIES YOU
GET MASSIVE FIBROSIS, THEY
ATTRACT MURINE NEUTROPHILS, THE
ONLY IMMUNE CELL LEFT IN THE
IMMUNODEFICIENT NSG MOUSE,
PRODUCE A TREMENDOUS AMOUNT OF
MUCINS.
THAT'S JUST AT THE WHOLE LIBRARY
LEVEL.
YOU CAN USE SINGLE CELL --
BECAUSE THESE ARE STEM CELLS
THEY ARE P 63 POSITIVE, AS IS
THE NORMAL LUNG STEM CELL.
YOU CAN USE FACT SORTING TO
SINGLE CELLS, THEY ARE HIGHLY
CLONOGENIC, YOU CAN EXPAND THEM
IN INFINITE MANNER AND LOOK AT
THEIR PROPERTIES.
THEY ARE CLUSTERED AS STEM CELLS
BUT WHEN YOU DIFFERENTIATE THEM
THEY ALL HAVE THESE DIFFERENT
POPULATIONS.
WE'VE BEEN ABLE TO IDENTIFY
THESE SIX POPULATIONS, NORMAL
AND FIVE VARIANTS.
SO WHEN YOU START EXAMINING
THESE AT A SINGLE CLONE LEVEL,
YOU REALIZE THAT CLONE 1 IS THE
NORMAL ONE, YOU KNOW, CLONE 2
GIVES A VERY SIMILAR EPITHELIUM.
IN FACT NORMAL DISTAL AIRWAY
EPITHELIUM.
CLONE 3 AND 4 GIVE RISE TO
GOBLET CELL METAPLASIA, AND
CLONES 5 AND 6 GIVE RISE TO
SQUAMOUS, ALL FIT CRITERIA FOR
STEM CELLS, UNIFORMLY EXPRESS
P62, THE STEM CELLMARKER.
THEY ARE INTRINSICALLY IMMORTAL,
NOT THE FIRST STEP TO
TRANSFORMATION, WE'RE NOW
FINDING THIS LIKE EMBRYONIC STEM
CELLS THESE ARE IMMORTAL.
VERY HIGH CLONOGENICICITY, IN
THIS CASE 50%, THAT NUMBER
DOESN'T CHANGE WITH INCREASED
PASSAGES.
THEY HAVE GENOMIC STABILITY.
ABSENCE OF COPY-NUMBER VARIATION
OR SIGNIFICANT SINGLE-NUCLEOTIDE
VARIATION.
LOOK AT THESE GENOMES OF ALL OF
THESE.
THERE'S NO COPY-NUMBER
VARIATION, VERY FEW SOMATIC
SINGLE NUCLEOTIDE POLYMORPHISMS,
AND YOU CAN GROW THESE CELLS
FOR -- THIS IS PASSAGE 25, WHICH
IS ROUGHLY 250 DAYS,
DIFFERENTIATE THEM, AND THEY
DON'T GET CONFUSED.
THEY ALWAYS KNOW WHAT THEY
SHOULD DO.
IN THIS CASE GOBLET CELL
METAPLASIA, SQUAMOUS CELL FOR
THESE TWO, APPARENTLY NORMAL
DISTAL AIRWAY EPITHELIUM.
>> FIVE MINUTE WARNING.
>> ALL OF THESE -- HERE IS P62
STEM CELLS IN THE NORMAL LUNG.
HERE IS THE ONES WE SEE A
SQUAMOUS CELL METAPLASIA AND
GOBLET CELL METAPLASIA.
THIS PRO-INFLAMMATORY OF VARIANT
2, 4, AND 6, THAT'S REFLECTED IN
THEIR GENE EXPRESSION PROFILES
AND MANY OF THESE ARE PART OF
INNATE IMMUNE RESPONSE.
YOU CAN SEE RESPONSES TO
L ESHMANIASIS, WE THINK THESE
ARE INTRINSIC PART.
THESE PRO-INFLAMMATORY ONES
DRIVE THE ACTIVATION OF
HUVECs, FIRST SITE IN
LEUKOCYTE ROLLING.
FIBROSIS ONES TRIGGER FIBROSIS
IN VITRO AND IN VIVO.
IMPORTANTLY, IF YOU NOW CORRECT
THE PROPERTIES, COMPLEMENT THE
CFTR MUTATION IN THESE, AND JOHN
ENGELHARDT AND GROUP HAVE DONE
THE BIOPHYSICS ON THIS, THESE
ARE CORRECTED.
YOU PUT THE SAME CORRECTED ONES
BACK INTO MICE.
THEY ARE STILL PRO-INFLAMMATORY.
GENE EXPRESSION PROFILES ARE
STILL PRO-INFLAMMATORY.
HASN'T CHANGED THAT AT ALL.
THE SAME WITH THE ACTIVATION OF
HUVACs, THERE'S NO CHANGE IN
THE ABILITY OF A NORMAL CFTR
GENE TO DO ANYTHING THERE.
AND IN VIVO WE PRETTY MUCH SEE
THE SAME THING.
IN THIS CASE IT'S THE
MODULATORS.
WE DON'T SEE ANY IMPACT
MODULATORS ON PATHOGENIC
FEATURES, STILL HYPER-MUCINOUS,
PRO-INFLAMMATORY, PRO FIBROTIC.
DO WE NEED A PLAN B FOR
ADVANCED PLAN?
WE BELIEVE THE VARIANTS DOMINATE
ADVANCED LUNG CONDITIONS.
IPF IS UNDER REVIEW RIGHT NOW.
AND CYSTIC FIBROSIS.
WE PREDICT THE DISEASE IS
MAINTAINED BY EXPANSION OF THESE
VARIANTS.
THE QUESTION IS CAN YOU
SELECTIVELY ELIMINATE THESE.
SO WE'VE NOW LEVERAGED THE
IMMORTALITY OF THESE CELLS TO DO
HIGH-THROUGHPUT DRUG SCREENING.
AND IT'S VERY EASY TO DO WITH
THESE CLONAL VARIANTS.
WE HAVE COME TO WHAT WE THINK
ARE EXCITING LEADS, DRUG
COMBINATIONS THAT DO NOT AFFECT
THE NORMAL DISTAL AIRWAY STEM
CELL BUT AFFECT PRETTY MUCH
ACROSS THESE LUNG CONDITIONS,
WHETHER IT'S COPD OR CYSTIC
FIBROSIS OR COVID VARIANTS,
SEVERE ASTHMA VARIANTS OR SINGLE
IPF VARIANT.
AND JUST FOLLOWING UP ON OUR
LAST SESSION, I THINK WE
ABSOLUTELY NEED TO BRING THIS
TECHNOLOGY INTO ANIMAL MODELS TO
VALIDATE THE CONCEPT THAT
PATHOGENIC VARIANTS IS A COMMON
THEME IN SEVERE DISEASE.
WE NEED TO MONITOR DYNAMICS OF
VARIANTS WITH DISEASE PROGRESS,
MONITOR DYNAMICS IN RESPONSE TO
ACUTE INFECTION, WE BELIEVE
THESE CELLS ARE ALL PREEXISTING.
THEY ARE PRESENT IN ALL OF US,
AT LOW LEVELS.
BUT IN RESPONSE TO ACUTE
INFECTION, WE IMAGINE THEY COME
UP, WE HAVEN'T DONE THOSE
EXPERIMENTS.
OF COURSE WE WANT TO ASSESS THE
IMPACT OF THE CFTR MODULATORS OR
PROSPECTIVE DRUGS WE AND OTHERS
WILL BE DEVELOPING AGAINST THESE
VARIANTS.
THIS IS JUST SOME OF THE WORK
WE'RE DOING WITH JOHN ENGELHARDT
AND COLLEAGUES.
WE'VE NOW DEVELOPED A NEW MEDIA
TO CAPTURE THE STEM CELL
VARIANTS OF THIS, AND GOD
WILLING, THAT WILL PROGRESS.
THIS HAS INVOLVED A TON OF
PEOPLE FROM UNIVERSITY OF IOWA,
M.D. ANDERSON CANCER CENTER,
HOUSTON METHODIST, NATIONAL
JEWISH, MARK METERSKY, GROUPS AT
UNC, CHRIS CRUM, A NUMBER OF
EXCELLENT SYNTHETIC CHEMISTS
HELPING US.
I WANT TO THANK MARA FOR
RESCUING US FROM CERTAIN DEMISE,
AND MAKING SURE WE'RE FUNDING
FOR ALL THEIR GENEROUS SUPPORT.
THANK YOU.
>> NEXT WE HAVE DR. VLADAR
TALKING.
>> CAN YOU ADVANCE THE SLIDES?
>> WE'RE GETTING YOUR SLIDES UP.
>> ALL RIGHT.
THANK YOU SO MUCH FOR THE
ORGANIZERS AND THE REST OF THE
SPEAKERS FOR THIS WONDERFUL
PROGRAM.
IT'S MY PLEASURE TO TELL YOU
ABOUT WHAT WE COULD LEARN FROM
THE EPITHELIAL TRANSCRIPTIONAL
AND RESPONSES TO MODULATOR
THERAPY IN CYSTIC FIBROSIS LUNG
DISEASE.
I HAVE NO -- NEXT SLIDE PLEASE.
I HAVE NO DISCLOSURES.
NEXT.
BUT I HAVE A LOT OF
ACKNOWLEDGMENTS, A TEAM OF
COLLABORATORS LED BY JEN TAYLOR
AND KATIE HISERT AND MAX
SEIBOLD.
NEXT.
ALL RIGHT.
I WILL START WITH THE PROBLEM
THAT WE'RE TRYING TO ADDRESS
WHICH IS THE EXTENSIVE
STRUCTURAL AND FUNCTIONAL DEFECT
CHARACTERIZED EPITHELIUM.
AS ILLUSTRATED BY SCANNING
IMAGES OF THE APICAL SURFACE OF
TURBINATES, CF AIR WAY FROM A
SINGLE DONOR IS HIGHLY VARIABLE
RANGING FROM NEARLY NORMAL TO
HIGHLY ABNORMAL.
THESE ARE ASSOCIATED WITH
DISEASE PHENOTYPES AS WELL.
THERE'S SOME EVIDENCE THAT SOME
TYPE OR EXTENT OF REMODELING MAY
BE IRREVERSIBLE.
WE PRIMARILY STUDY CF EPITHELIUM
AND I'LL COME BACK TO
SPECIFICALLY ADDRESS THE
RELATIONSHIP AND RELEVANCE OF
THAT TO LOWER AIRWAY DISEASE.
NEXT.
NEXT SLIDE.
I WILL BRIEFLY MENTION THAT
REMODELING PHENOTYPES IN VIVO
AIRWAYS ARE REFLECTED IN PRIMARY
CULTURE, ISOLATED FROM DONOR
TISSUE TO STUDY FUNCTIONAL
OUTCOMES.
YOU CAN SEE DISEASE DONOR TISSUE
LEADS TO POORLY DIFFERENTIATED
CULTURES.
NEXT PLEASE.
WHILE REMODELING MECHANISMS ARE
NOT COMPLETELY WELL UNDERSTOOD,
THEY ARE LIKELY TO BE COMPLEX,
THIS IS HOW I THINK ABOUT HOW IT
EVOLVES AND HOW CORRECTORS MAY
PLAY A ROLE IN IMPACTING IT.
CAN YOU JUST KEEP MOVING THROUGH
THE ANIMATIONS?
INC,
WE START IN EARLY LIFE,
DIFFICULTY CLEARING MUCUS,
LEADING TO REMODELING.
IT REMAINS UNKNOWN TO WHAT
EXTENT CF MODULATOR THERAPY
WHICH IS THE TRIPLE COMBINATION
IS ABLE TO RECTIFY THESE CHANGES
ESPECIALLY WHEN INITIATED IN
ADULT POPULATION WITH
ESTABLISHED DISEASE.
NEXT PLEASE.
WITH THIS WORKSHOP IN MIND, I
OUTLINED FIVE BIG GAPS FOR
DISCUSSION CONCERNING INITIATING
MODULATORS IN FOLKS WITH
ESTABLISHED DISEASE.
FIRST EPITHELIAL REMODELING,
DOES IT IMPROVE UPON STARTING
MODULATORS?
SECOND, WHAT IS EXTENT OF THIS
IMPROVEMENT OVER TIME?
AND IMPORTANTLY, HOW HEALTHY DO
WE GET COMPARED TO HEALTHY
INDIVIDUALS?
THIRD AND FOURTH, HOW USEFUL ARE
TRANSCRIPT OMIC METRICS, PRIMARY
CULTURE MODELS, CHARACTERIZING
AND MONITORING CF LUNG DISEASE
RESPONSE TO MODULATORS.
FINALLY HOW DO WE USE THIS INFO
AND APPROACHES CURRENTLY BEING
DEVELOPED TO ASSESS FUTURE
MODULATOR OUTCOME WITH MILD OR
DISEASE OR AGING CF IN THE
FUTURE.
I STRUCTURED THE TALK ADDRESS
THESE QUESTIONS.
NEXT PLEASE.
AND THEN JUST PLEASE DO ALL THE
ANIMATIONS.
ALL RIGHT.
I WILL JUMP INTO THIS.
STUDIES TO ASSESS MODULATOR
RESPONSE IN ADULT COHORT.
FIRST IS A TIMECOURSE RESPONSE
STUDY IN COLLABORATION TO TEST
HYPOTHESIS MODULATORS WILL LEAD
TO IMPROVEMENT IN CF-RELATED
SINUS DISEASE AND
PATIENT-REPORTED OUTCOMES AS
WELL AS ACCOMPANYING
TRANSCRIPTOMICS AND FUNCTIONAL
CHANGES IN THE MUCOSA AT SIX
MONTHS AND TWO YEARS COMPARED TO
BASELINE.
CLINICAL STUDIES HAVE BEEN
CARRIED OUT AND I WOULD LIKE TO
REFER YOU TO THE EXCELLENT
PAPERS BELOW WHICH DEMONSTRATE
TRUE TO ITS NATURE MODULATORS
LEAD TO SUBSTANTIAL IMPROVEMENT
IN SINUS DISEASE.
I WILL TALK ABOUT THE THIRD AIM
OF THE STUDY, CARRIED OUT BY MY
LAB.
WE HAVE A SECOND INDEPENDENT
STUDY WHICH WE CONDUCTED WITH
KATIE HISERT AND MAX TO TEST
HYPOTHESIS THE UP -- EPITHELIUM
WILL HAVE ALTERED FUNCTION
COMPARED TO HEALTHY INDIVIDUALS.
NEXT PLEASE.
BRIEFLY, THIS IS THE MODULATOR
TIME COURSE, WE COLLECTED NASAL
BRUSH BIOPSIES FROM 25 SUBJECTS,
RED FOR BULK RNAseq, LEFT WAS
USED FOR PRIMARY CULTURE.
AND THEN WE HAVE OUR MODULATOR
VERSUS HEALTHY STUDY WHERE WE
ENROLLED ADDITIONAL 10 CF
SUBJECTS AT SIX MONTHS AFTER ETI
THERAPY, AND NINE HEALTHY AGE
MATCHED SUBJECTS, RIGHT CARRIED
OUT SINGLE CELL SEQUENCING, LEFT
NOSE DID CULTURES.
THEN LET'S START WITH OUR FIRST
KNOWLEDGE GAP, DO MODULATORS
RECTIFY INFLAMMATORY REMODELING,
TIME COURSE DATA INDICATES IT
DOES ALTHOUGH RESPONSE IS HIGHLY
VARIABLE.
I'M SHOWING ONLY THE DATA FOR
THE SIX MONTHS TO BASELINE WHICH
LED TO 1500 DIFFERENTIALLY
REGULATED GENES, DOMINATED BY
REDUCED NEUTROPHILIC
INFILTRATION.
THIS IS A HEAT MAP THOSE THE
GENES, BLUE IS DOWN, RED IS UP.
GENES ARE BY ROWS, SUBJECT BY
COLUMNS.
YOU CAN SEE THERE IS QUITE A
HETEROGENEOUS RESPONSE AMONGST
THE SUBJECTS WHICH WE ASSIGN TO
GROUPS, A, B,C, AND D.
GOOD NEWS, VAST MAJORITY OF
SUBJECTS, THOSE IN B-D,
DECREASED INFLAMMATION, HALLMARK
OF ABERRANT STRUCTURE,
CONSISTENT WITH IMPROVED
REMODELING.
UNDERSTANDING VARIABILITY AND
DURABILITY OF THIS RESPONSE OVER
TIME AND MECHANISMS THAT DRIVE
CHANGES WILL BE CRITICAL TO
DECIPHER IN THE FUTURE AND
HOPEFULLY BASED ON HYPOTHESIS WE
CAN GENERATE FROM EXPRESSION
DATA.
NEXT PLEASE.
THE NEXT SECOND CRITICAL
KNOWLEDGE GAP IS TO KNOW WHAT IS
THE EXTENT OF THE IMPROVEMENT
OVER TIME, IMPORTANTLY WHAT IS
IT COMPARED TO HEALTHY
INDIVIDUALS THAT ARE AGE
MATCHED.
I'LL START WITH DISCLAIMER, OUR
TWO-YEAR SAMPLES HAVE BEEN
SEQUENCED, I CAN'T COMMENT ON
LONG-TERM CHANGES AND HOPEFULLY
WILL HAVE THOSE RESULTS.
WE'VE BEEN ABLE TO GENERATE
ROBUST SINGLE CELL TRANSCRIPT
OPENS FROM IMMUNE CELL
POPULATIONS, FROM CF SUBJECTS
ABOUT SIX MONTHS ON MODULATORS
AND HEALTHY INDIVIDUALS.
THIS PROJECTION SHOWS CELL
STATES RECOVERED IN OUR
SUBJECTS.
NEXT PLEASE.
PERHAPS NOT SURPRISINGLY WHAT WE
FOUND IS THAT THE CF EPITHELIUM
REMAINED DISTINCT FROM HEALTHY,
TO OUTLINE THREE EXAMPLES I'M
SHOWING HERE THE EXPRESSION OF
SPECIFIC MARKER GENES LAID ON
HEALTHY VERSUS CF CELL
POPULATIONS TO SHOW THAT FIRST
THE CF SINONASAL MUCOSA DISPLACE
SUBSTANTIAL NEUTROPHIL DOMINANT
INFLAMMATION, HALLMARKS OF
SQUAMOUS METAPLASIA.
NEXT PLEASE.
>> FIVE-MINUTE WARNING.
>> TO MORE BROADLY DEFINE
MECHANISMS THAT DRIVE THESE
CHANGES CARRIED OUT CELL CHAT
ANALYSIS, CELL-CELL SIGNALING
RELATIONSHIP.
I DON'T EXPECT YOU TO INTERPRET
THE DATA ON THE SCREEN BUT THIS
IS JUST TO SHOW THAT WE DETECT
SIGNIFICANT DIFFERENCE IN IMMUNE
SIGNALING AND EPITHELIAL
DIFFERENTIAL PATHWAYS, HOPING TO
USE MODELS TO PICK APART
MECHANISTIC DETAILS.
NEXT PLEASE.
THEN THIS IS A GREAT SEGUE INTO
THE THIRD KNOWLEDGE GAP, HOW
WELL THE TRANSCRIPTOMIC AND
PRIMARY CULTURE DATA REFLECT
MODULATOR RESPONSE IN PEOPLE.
GOING BACK TO OUR MODULATOR
RESPONSE TIME COURSE WE CARRIED
OUT EXTENSIVE ANALYSES TO SEE IF
THERE'S CORRELATION BETWEEN OUR
GENE EXPRESSION DATA AND ANY OF
THE SUBJECT CHARACTERISTICS OR
CLINICAL AND PATIENT-REPORTED
OUTCOMES.
FOCUSING ON TWO CRITICAL
METRICS, NEXT PLEASE, WHICH IS
MEASURE OF SINUS DISEASE
SEVERITY BY SCAN WE SAW
SUBSTANTIAL IMPROVEMENT IN MOST
BUT ONLY DETECTED SIGNIFICANT
CORRELATION WITH CHANGES IN
SINUS DISEASE SEVERITY.
IN FACT WE WERE ABLE TO SHOW
THIS CAN BE DRIVEN AND DRILLED
DOWN TO A A SINGLE GENE PROK2,
FUNCTION NOT CLEAR BUT SHOWN TO
BE UPREGULATED IN NEUTROPHILS BY
GSFT AND TO BE HIGHLY EXPRESSED
IN THE CF LUNG AND SUGGEST LOWER
PROK2 REPRESENTS REDUCTION OF
INFLAMMATION, AND WHY WE DIDN'T
DESECRETARY PROK 1A SUBJECT
LATER.
ADDRESSING PRIMARY CULTURES TO
STUDY MODULATOR RESPONSE USED
CULTURE MODEL, NOT OVERLY
SUPPORTIVE OF DIFFERENTIATION
LIKE COMMERCIAL FORMULATIONS AND
FOUND CONSISTENT FOR
TRANSCRIPTOMIC DATA SIX MONTH
CULTURES IMPROVED, CILIATED CELL
DIVERSITY, -- DIFFERENTIATION.
HERE INTERESTINGLY CULTURES ETI
COMPOUND TREATED IN VITRO HAD AN
EFFECT ON DIFFERENTIATION, VERY
INTERESTING TO UNDERSTAND IN THE
FUTURE, SUGGESTING STEM CELL
POOL ISOLATED FROM THE SAME AREA
SIX MONTHS APART HAVE IMPROVED
DIFFERENTIATION CAPACITY AT SIX
MONTHS COMPARED TO BASELINE AND
WE'RE ACTIVELY CHARACTERIZING
COMPOSITION AND FUNCTION OF THIS
POPULATION AS WELL AS PATHWAYS
THAT CONTROL DIFFERENTIATION
WHICH WILL BE CRITICAL AS WE
CONSIDER THESE FOR FUTURE GENE
THERAPY APPLICATIONS FOR
AGING-RELATED PHENOTYPES.
NEXT ONE PLEASE.
BRIEFLY I WANT TO TOUCH ON THIS
STUDY OF THE SINONASAL
EPITHELIUM AS PROXY FOR CF LUNG
DISEASE.
WE USE NASAL BRUSH BIOPSIES, THE
ARGUMENT FOR USE RESTS IN
UNIFIED AIR WAY HYPOTHESIS,
UPPER AND LOWER AIRWAYS COMPRISE
SINGLE UNIT AND ARISING FROM
COMMON INFLAMMATORY PROCESS, NOT
THAT THE PHENOMENON THERE'S BOTH
SINONASAL AND LUNG DISEASE BUT
TRULY A UNIFIED MECHANISM.
AND THERE'S REALLY A LOT TO BE
SAID FOR THE USE OF NASAL
BRUSHES CONSISTENT, IT'S EASY,
ALLOWS LONGITUDINAL SAMPLING.
NEXT PLEASE.
AND ONE MORE.
AND IT'S WIDESPREAD AND THERE'S
BEEN A GOOD PRECEDENT FOR THEIR
USE IN CF.
AND OTHER DISEASES LIKE ASTHMA,
CAREFUL STUDIES COMPARED NASAL
AND BRONCHIAL EPITHELIA FROM THE
SAME DONORS AND DIFFERENT WAYS
AND FOUND THEM TO BE REASONABLY
SIMILAR BUT NOT THE SAME.
WHICH THEN LEADS US TO CONSIDER
THIS REALLY HASN'T BEEN
CAREFULLY EVALUATED IN CF IN ALL
CASES WHERE THERE'S EVIDENCE
THAT SINONASAL INFLAMMATION
ESPECIALLY MICROBIOME MAY BE
QUITE DISTINCT.
>> ONE-MINUTE WARNING.
>> ALL RIGHT.
SO THEN WITH THAT I WILL
CONCLUDE THAT OUR DATA INDICATE
THAT MODULATOR INITIATION PEOPLE
WITH CF ESTABLISHED DISEASE
LEADS TO IMPROVEMENT IN
REMODELING BUT TRANSCRIPTIONAL
RESPONSES ARE VARIABLE AND NOT
FULLY CORRELATED.
NEXT.
AND WITH MY FINAL SLIDE, I DREW
A FEW WHAT I THINK ARE PRIORITY
AREAS THAT WILL HELP INCREASE
OUR UNDERSTANDING OF LONG-TERM
MODULATOR USE.
WE NEED TO UNDERSTAND WHAT
MECHANISMS DRIVE REMODELING, HOW
MODULATORS RECTIFY CHANGES.
IRREVERSIBLE CHANGES LIKE THOSE
ASSOCIATED WITH BRONCHIAL
REGIONS, CAN THIS REVEAL EARLY
SIGNS OF NEW LUNG DISEASE.
AS PEOPLE WILL LIVE LONGER AND
TO POTENTIALLY BENEFIT FROM GENE
THERAPY, WE HAVE A LOT TO DO IN
TERMS OF METHODOLOGY, AND
CROSS-COMPARISON OR MULTIOMICS
WITH BE CRITICAL.
IF ANYBODY IS INTERESTED IN
COLLABORATING PLEASE GET IN
TOUCH.
THIS IS THE END OF MY
PRESENTATION.
THANK FOR YOUR TIME.
NEXT SPEAKER IS DR. PRADEEP
SINGH.
>> I'M GETTING A MESSAGE SAYING
THE HOST STOPPED ME FROM SHOWING
VIDEO.
THERE WE GO.
GREAT.
THANKS.
CAN YOU SEE ME AND HEAR ME OKAY?
>> YES.
>> ALL RIGHT.
THANK YOU.
I'M GOING TO TALK TODAY ABOUT CF
MODULATORS AND EFFECTS ON CF
INFECTION.
I THINK A LOT OF US WOULD AGREE
CF INFECTIONS ARE PROBABLY AMONG
THE MOST IMPORTANT CLINICAL
MANIFESTATIONS OF CYSTIC
FIBROSIS BUT WE REALLY DON'T
REALLY KNOW YET HOW MODULATORS
AFFECT INFECTION OUTCOMES.
THERE'S BEEN A NUMBER OF SMALL
STUDIES THAT LOOK AT SPUTUM
PROSPECTIVELY TO MEASURE
MICROBIOLOGY AFTER MODULATORS
AND SOME SHOW MODULATORS REDUCE
SPUTUM BACTERIA, OTHER STUDIES
HAVE SHOWN NO CHANGE AFTER
MODULATOR TREATMENT.
I'LL START AND GIVE SOME HIGH
LEVEL RESULTS FROM THE PROMISE
OF STUDY, PROMISE OF
MICROBIOLOGY SUBSTUDY, PROMISE
IS LED BY STEVE ROWE AND DAVE
NICHOLS, AND THIS STUDY
COLLECTED INDUCED SPUTUM BEFORE
AND DURING ETI TREATMENT,
SCHEDULED TO GO ON NOW FOR FOUR
YEARS.
RIGHT NOW I'LL TALK ABOUT THE
FIRST SIX MONTHS OF DATA.
I THINK NOTABLE POINT THIS IS A
LARGE STUDY, THE LARGEST STUDY
WE HAVE SO FAR LOOKING
PROSPECTIVELY AT WHAT HAPPENS TO
SPUTUM MICROBIOLOGY AFTER
MODULATORS, THERE'S A WIDE RANGE
OF STUDY PARTICIPANTS.
YOU CAN SEE THE FEV1 FROM LOW TO
HIGH, AN IMPORTANT POINT IS THIS
STUDY INCLUDED PATIENTS THAT DID
AND DID NOT HAVE OR MEET
DEFINITION OF CHRONIC INFECTION.
IT WAS A REAL WORLD STUDY
LOOKING AT ALL COMERS INITIATING
ETI.
AS I SAID, THIS IS THE FIRST SIX
MONTHS OF A TWO-YEAR NOW GOING
TO BE FOUR-YEAR STUDY.
TO START WITH I THINK ONE OF THE
MOST STRIKING FINDINGS IS THE
EFFECTS ON SPUTUM DENSITY OF KEY
CF PATHOGENS.
WHAT'S PLOTTED ON THE Y-AXIS IS
THE GRAMS OF SPUTUM, SORRY, CFU
PER GRAM OF SPUTUM ON A LOG
SCALE.
X-AXIS IS TIME AFTER STARTING
ETI.
THIS FIRST PANEL SHOALS EFFECT
ON STAPH AUREUS IN THIS COHORT.
YOU CAN SEE THERE'S A MARKED
REDUCTION THAT OCCURS IN THE
FIRST MONTH IN STAPH AUREUS CFU
DENSITY, MAINTAINED THROUGHOUT
SIX-MONTH OBSERVATION PERIOD.
SIMILAR WITH P AERUGINOSA, A
HUNDRED FOLD IN THE FIRST MONTH,
STABILITY AFTER THAT ON AVERAGE,
AND MORE PRONOUNCED BUT SIMILAR
EFFECT ON S MALTOPHILIA.
WHEN WE LOOK AT MAGNITUDE OF
THESE DECLINES IN THE FIRST
MONTH OF TREATMENT THEY ARE
PRONOUNCED.
YOU'RE SEEING CONSISTENT
IRRESPECTIVE OF PATHOGEN, YOU'RE
SEEING TWO TO THREE LOG TEN
REDUCTION OF SPUTUM CFU DENSITY
IN FIRST MONTH OF TREATMENT.
UNFORTUNATELY SO FAR WE'VE NOT
OBSERVED THAT A LARGE NUMBER OF
SUBJECTS BECOME PERSISTENTLY
CULTURE NEGATIVE.
THIS IS ONLY THE SIX-MONTH
INTERIM REPORT SO WE'LL NEED
MORE DATA TO REALLY ANSWER THIS
QUESTION DEFINITIVELY, WHETHER
PATIENTS ARE CONVERTING TO
CULTURE NEGATIVE BUT LET ME SHOW
YOU WHAT WE'VE SEEN SO FAR.
WE HAVE 49 SUBJECTS RIGHT NOW,
P.A. POSITIVE, CULTURE POSITIVE
AT STUDY ENTRY, PROVIDED AT
LEAST TWO SPUTUM SAMPLES,
ADDITIONAL SAMPLES OVER THE
FIRST SIX MONTHS OF TREATMENT,
THOSE 49 REPRESENT GREEN DOTS,
EACH IS A SUBJECT.
WE LOOK AT SUBJECTS THAT BECAME
REPEATEDLY CULTURE NEGATIVE, IT
WAS RELATIVELY SMALL.
ONLY 14 OUT OF 49.
WE SEE EVEN WORSE OUTCOMES I
THINK FOR STAPH AUREUS.
83 SUBJECTS REPRESENTED BY THESE
GREEN DOTS TO CULTURE POSITIVE
FOR STAPH AUREUS ON STUDY ENTRY,
GAVE WHO SAMPLES, SO FAR ONLY 6
HAVE BECOME REPEATEDLY CULTURE
NEGATIVE.
MOST PEOPLE WHO COME IN A
PATHOGEN APPEAR TO RETAIN THAT
PATHOGEN AT LEAST THE FIRST SIX
MONTHS OF OBSERVATION.
SO, THAT WAS SOME CULTURE-BASED
DATA.
WE'VE LOOKED USING DNA METHODS
TO ASK MORE BROADLY HOW DOES ETI
CHANGE ALL THE OTHER ORGANISMS
THAT CAN BE DETECTED IN SPUTUM
SAMPLES.
WE SEQUENCED 16S R-RNA AND
CALCULATED TAXA ABSOLUTE
ABUNDANCE LEVELS BY MULTIPLYING
TIMES INDIVIDUAL GENERA, ON THE
Y-AXIS I'M SHOWING CHANGE IN THE
ABSOLUTE ABUNDANCE IN THESE
ORGANISMS, THAT WERE PRESENT AT
GREATER THAN 1% RELATIVE
ABUNDANCE IN THE STARTING SPUTUM
SAMPLE, PRE-TREATMENT SPUTUM
SAMPLE, THOSE ORGANISMS.
AND THE Y-AXIS IS PLOTTED CHANGE
IN ABSOLUTE ABUNDANCE AFTER A
MONTH.
THIS LOOKS SIMILAR TO WHAT
OCCURS AT THREE MONTHS AND SIX
MONTHS.
IT'S REPRESENTATIVE OF THE
OVERALL CHANGE.
WHAT YOU CAN SEE IS THAT THERE'S
A CLEAR DIFFERENTIATION IN
RESPONSE TO ETI.
WE LOOK AT THE CF PATHOGENS
PLOTTED ON THE RIGHT SIDE.
YOU CAN SEE ALL OF THEM WITH
EXCEPTION ONE EXHIBIT CHANGES,
OTHER LIKE STREP, PREVOTELLA,
GAMELLA, PART OF THE ORAL
MICROBIOME, DON'T CHANGE AT ALL
SIGNIFICANTLY AFTER ETI IS
INITIATED.
LOOKING ANOTHER WAY BY GROUPING
TOGETHER TRADITIONAL PATHOGENS
AND OTHER BACTERIA, AND WHEN WE
DO THIS NOW I'M SHOWING ON THE
Y-AXIS CALCULATED ABSOLUTE
ABUNDANCE IN GENOME COPY PER MIL
OF TRADITIONAL PATHOGENS GROUPED
TOGETHER.
YOU CAN SEE THE LIST AT THE TOP.
AGAIN YOU'RE SEEING ABOUT A 1
1/2-ISH, 2-LOG REDUCTION AFTER A
MONTH, THAT STAYS STABLE.
ALL THE OTHER BACTERIA NOT
TRADITIONALLY CONSIDERED CF
PATHOGENS DIDN'T EXHIBIT ANY
CHANGE.
TO SUMMARIZE SO FAR, ETI
TREATMENT REDUCED ALL CF
PATHOGENS BY 2 OR 3 LOGS,
INCLUDING STAPH AUREUS,
PSEUDOMONAS, AND A SMALL NUMBER
OF PATIENTS WHO HAD OTHER
SPECIES.
WHEN WE LOOKED BY SEQUENCING
FOUND THE SAME THING FOR THE CF
PATHOGENS, ETI REDUCED ABSOLUTE
ABUNDANCE OF TRADITIONAL
PATHOGEN SPUTUM, BUT DIDN'T
PRODUCE CHANGE OR PRODUCED NO
CHANGE IN ANY OF THE OTHER GENRE
DETECTED THERE.
I DIDN'T HAVE TIME TO SHOW THIS
DATA BUT ETI DID PRODUCE A
SLIGHT INCREASE IN SPUTUM
MICROBIAL DIVERSITY BUT WHEN WE
INCREASE, THIS CHANGE OR
INCREASE IN DIVERSITY IS ALL
DRIVEN BY REDUCTION IN THE
TRADITIONAL CF PATHOGENS AFTER
ETI TREATMENT.
I'M GOING TO END WITH FIVE KEY
QUESTIONS ABOUT CF INFECTIONS IN
THE POST-MODULATOR ERA.
FIRST IMPORTANT QUESTION HOW
DURABLE ARE PATHOGEN REDUCTIONS?
IS THAT GOING TO BE THE NEW
NORMAL OR IS IT A POSSIBILITY
THEY COULD IMPROVE FURTHER OR
MAYBE EVEN GET WORSE?
SO WE HAVE DATA FROM THE DUBLIN
STUDY GROUP, HISERT WAS FIRST
OFF ON SOME.
THAT SHOWED -- A SMALL STUDY, 12
PEOPLE TOTAL, THAT AFTER ABOUT A
YEAR, SOMETIME BETWEEN A YEAR
AND A HALF AND TWO YEARS AFTER
STARTING IVACAFTOR SUBJECTS WITH
THE MUTATIONS EXHIBITED A
REBOUND IN PSEUDOMONAS DENSITY
FOUND IN SPUTUM.
Y-AXIS IS PSEUDOMONAS DENSITY
MEASURED BY CULTURE, X-AXIS IS
TIME.
THIS IS IN YEARS NOW.
WE SAW INITIAL DECLINE LIKE WE
SAW WITH ETI, AND THEN REBOUND
INCREASED DENSITY.
WE DON'T FLOW IF THAT'S GOING TO
HAPPEN WITH ETI OR NOT.
THE NADIR WAS AROUND A YEAR,
DON'T KNOW EXACTLY WHEN,
FOLLOWED BY REBOUND.
WE ALSO SAW SIMILAR PHENOMENA
WITH INFLAMMATION.
ON THE Y-AXIS NEUTROPHIL
ELASTICS LEVEL IN SPUTUM
MEASURED ON LOG SCALE, X-AXIS IS
TIME IN YEARS.
WE SAW SIMILAR REBOUND OCCURRING
A BIT LATER IT APPEARS IN SPUTUM
INFLAMMATION.
SECOND KEY QUESTION RAISED BY
THE DATA AND RELEVANT TO POST
MODULATOR ERA, WHY DO WE SEE
THESE MARKED REDUCTION IN
PATHOGENS BRUCE TROMBERG ARE BUT
-- BUT OTHER TAXA REMAIN
CONSTANT.
ONE POSSIBILITY IS THAT ETI,
MODULATORS IN GENERAL, CORRECT
DEFENSES THAT ONLY ACT ON
PATHOGENS, LEAVE THE OTHER BUGS
UNTOUCHED.
MODULATORS IMPROVE CLEARANCE AND
SHOULD CLEAR BACTERIA,
MODULATORS ARE SHOWN TO REDUCE
MUCUS PLUGGING, SHOULD REDUCE
GROWTH NICHE FOR ANAEROBES.
ANOTHER POSSIBILITY PATHOGENS
ARE COMING LARGELY FROM THE LUNG
WHERE ETI IS WORKING AND
IMPROVING HOST DEFENSES, WHEREAS
THE OTHER BACTERIA WE FIND IN
SPUTUM ARE LARGELY COMING FROM
THE ORAL PHARYNX.
WE KNOW SALIVA CONTAINS
ASTRONOMICAL CONCENTRATIONS, 10
TO THE 8th, 10 TO THE 10th
IN SOME STUDIES.
IF YOU REDUCE PATHOGENS IN THE
LUNG, THE OTHER BACTERIA IN THE
SPUTUM CONTAMINANTS WERE
UNCHANGED, NET EFFECT, REDUCED
PATHOGENS BUT OTHER BACTERIA
UNCHANGED IN ABSOLUTE ABUNDANCE.
QUESTION 3, HAVE THESE SUBJECTS
WHO CONVERTED TO
CULTURE-NEGATIVITY, HAVE THEY
TRULY CLEARED THEIR INFECTION?
ARE THEY INFECTION FREE? IT'S A
TOUGH QUESTION TO ANSWER WITH
SPUTUM BUT WE TRY TO GET MORE
INFORMATION ABOUT THAT BY
STUDYING SPUTUM OF SUBJECT WHO
IS CONVERTED TO CULTURE NEGATIVE
AFTER ETI WITH VERY SENSITIVE
SPECIES-SPECIFIC DROPLET DIGITAL
PCR STUDIES ON CULTURE NEGATIVE
SPUTUMS.
>> TWO-MINUTE WARNING.
>> FIVE OR ONE?
>> TWO-MINUTE WARNING.
>> THANKS.
THAT'S PERFECT.
I'VE SHOWN THIS DOT PLOT, THESE
ARE THE PATIENTS WHO CAME IN
WITH PSEUDOMONAS CULTURE
POSITIVE.
THESE ARE THE PATIENTS, 14 THAT
BECAME REPEATEDLY CULTURE
NEGATIVE, WHEN WE LOOK BY
SENSITIVE DIGITAL DROP PCR NOW
ONLY FIVE SUBJECTS WHO ARE
DIGITAL PCR NEGATIVE FOR P
AERUGINOSA.
SIMILAR WITH STAPH AUREUS.
HERE IS 6 THAT BECAME CULTURE
NEGATIVE, NOW WHEN I LOOK WITH
SENSITIVE DIGITAL DROPLET PCR ON
SAMPLES ONLY 3 OF THESE SUBJECTS
WERE NEGATIVE FOR STAPH AUREUS
SUGGESTING THERE MAY BE
PERSISTENT INFECTION EVEN IN
CULTURE NEGATIVE SUBJECTS.
ANOTHER IMPORTANT POINT IS THAT
WE HAVE OBSERVED SMALL NUMBER OF
SUBJECTS WHO DEVELOP WHAT
APPEARS TO BE NEW P.A. AND S A
INFECTIONS AFTER STARTING ETI.
PREVIOUS DATA SUGGESTS THEY WERE
UNINFECTED, AND MAYBE THEY HAVE
DEVELOPED NEW INFECTIONS
SUGGESTING PERSISTENT DEFECT.
SO, QUESTION 4, WHY DO MOST
PATIENTS REMAIN PERSISTENTLY
INFECTED, DESPITE MARKET
IMPROVEMENT IN CFTR ACTIVITY?
THE LEADING HYPOTHESIS IN THE
FIELD IS DUE TO SEVERE AREAS OF
LUNG DAMAGE, THESE REMAIN
INFECTED WHEREAS THE MILD AREAS
CLEAR, AND WE'VE STARTED TO
INVESTIGATE THAT USING
BRONCHOSCOPY TO SAMPLE MOST AND
LEAST DAMAGED REGIONS.
WE'RE FINDING A PATTERN IN A
SUBJECT EITHER ALL THE AREAS
CLEAR OR NONE OF THE AREAS
CLEAR.
SO THE SEVERELY DAMAGED REGIONS
ARE MARKED IN RED, MILDEST
DAMAGE REGION IN YELLOW, AND YOU
CAN SEE SUBJECT A ALL REGIONS
CLEAR, SUBJECT B NONE OF THE
REGIONS CLEARED.
HERE IS CLEARANCE DATABASED ON
HIGHEST DAMAGED REGIONS AND
LOWEST DAMAGED REGIONS AND WE
SEE ABOUT 40% OF REGIONS CLEARED
REGARDLESS OF MILD OR SEVERE
DISEASE.
THE LAST QUESTION IS DOES
INFLAMMATION PERSIST IN LUNG
REGIONS THAT CLEAR INFECTION?
AGAIN WE'VE USED A BRONCO SCOPEY
STUDY, WE'VE MEASURED NEUTROPHIL
ELASTASE, AND WHAT WE FIND IS
THAT IN THE AREAS OF LUNG WHERE
P.A. PERSISTS WE CAN STILL SEE
ELEVATED LEVELS OF NEUTROPHIL
ELASTASE, THOSE WHO CLEAR DON'T
HAVE DETECTABLE LEVELS.
CONCLUDING, WE FOUND ETI
MARKEDLY REDUCES CF PATHOGENS IN
SPUTUM BUT MOST REMAIN
PERSISTENTLY INFECTED AND SOME
NEW INFECTIONS OCCUR.
POST-MODULATOR INFECTIONS MAY
NOT BE DUE TO COLONIZATION OF
HIGHLY DAMAGED LUNG REGIONS, A
SMALL STUDY, WE NEED LARGER
STUDIES TO REALLY INVESTIGATE
THIS IDEA.
IT'S A KEY POINT FOR THE FUTURE.
WE FOUND SO THAT ARE THAT
ELASTASE BECOMES UNDEFECT AL IN
REGIONS THAT CLEAR POST ETI, A
SMALL STUDY, NEED MORE WORK ON
THIS.
WE DON'T KNOW WHAT THE
DURABILITY OF RESPONSE AND
MECHANISM OF PERSISTENT
INFECTION AFTER MODULATOR
TREATMENT ARE AND THIS ALSO
NEEDS MORE STUDY.
I SHOWED SOME DATA FROM THE
PROMISE MICROBIOLOGY STUDY LED
DIE DAVE AND SARAH, SONIA,
MICHELE CONTRIBUTED, BAL STUDY
LED BY SAM AND COLLABORATORS AT
UNIVERSITY OF WASHINGTON,
UNIVERSITY OF IOWA
THANKS FOR YOUR ATTENTION.
>> I WANT TO THANK THE
ORGANIZERS FOR INVITING ME TO
PRESENT ON THE POTENTIAL
INTERSECTION OF ENDOCRINE
COMORBIDITIES AND MODULATOR
THERAPY.
AND FOR THE PURPOSES OF THIS
PRESENTATION I WILL HIGHLIGHT
DATA I THINK ARE RELEVANT FOR
ADDRESSING KNOWLEDGE GAPS IN
SEVERAL CONDITIONS.
AND THE FIRST IS CAN HIGHLY
EFFECTIVE MODULATOR THERAPY
IMPROVE, DELAY, EVEN PREVENT
CF-RELATED DIABETES?
CAN MODULATOR THERAPY INFECT
RELATED LOW BONE DENSITY AND
WHAT ARE UNDERLYING MECHANISMS
ARE WILL CHARACTERISTICS THAT
PORTEND FAVORABLE OUTCOMES, AND
WHAT IS THE TIME FRAME.
IN CONTRAST IS TRADITIONAL
PROTECTION AGAINST
CARDIOMETABOLIC AND
CARDIOVASCULAR RISK WE'VE LONG
CELEBRATED MITIGATED BY
MODULATOR THERAPY.
MANY OF US WERE EXCITED WHEN
CASE REPORTS IMPROVED GLUCOSE
EMERGED FOLLOWING IVACAFTOR.
HERE IS BELLIN, FIVE ADULTS WHO
UNDERWENT TESTING AND ACUTE
INSULIN RESPONSE, INDIVIDUALS
WITHOUT CFRD IMPROVEMENTS UNDER
ORAL AND INTRAVENOUS GLUCOSE
CONDITIONS.
BUT DATA WERE LESS COMPELLING IN
CFRD, SUGGESTING MINIMAL
FUNCTION MUST BE AVAILABLE IN
ORDER FOR MODULATOR THERAPY TO
IMPART IMPROVEMENTS.
U.S. AND U.K. REGISTRY DATA
DEMONSTRATED TRENDS IN LOWER
CFRD RATES OVER THE FOUR TO FIVE
YEARS AFTER INTRODUCTION OF
IVACAFTOR IN INDIVIDUALS WITH CF
COMPARED TO INDIVIDUALS WITH CF
NOT TREATED WITH IVACAFTOR SHOWN
ON THE RIGHT.
GIVEN THIS ENTHUSIASM LARGER
PERSPECTIVE SUBSTUDY WAS
INCLUDED IN A STUDY, 39
INDIVIDUALS WITH VARIABLE
GLUCOSE TOLERANCE AT BASELINE
UNDERWENT TWO-HOUR TESTING.
AND OF THE 30 COMPLETERS AT 12
MONTHS THERE DID NOT APPEAR TO
BE IMPROVEMENT IN OVERALL
GLUCOSE TOLERANCE.
AND THAT DATA IS CONFIRMED BY NO
IMPROVEMENTS IN FASTING GLUCOSE,
TWO HOUR GLUCOSE, GLUCOSE AREA
UNDER THE CURVE DURING THE OGTT
AND NEW IMPROVEMENT UNDER THE
CURVE.
THIS WAS NOT SURPRISING GIVEN
LESS ROBUST IMPACT ON CF
OUTCOMES.
SO DESPITE THIS INITIAL
DISAPPOINTMENT, WE REMAINED
HOPEFUL WE WOULD SEE
IMPROVEMENTS IN DIABETES-RELATED
OUTCOMES WITH ELEXACAFTOR AND
TEZA AND IVACAFTOR.
A STUDY USED CONTINUOUS GLUCOSE
MONITORING AND HERE AT THE
BOTTOM FOR THOSE LESS FAMILIAR
WITH THIS TOOL IS THREE-DAY
OUTPUT OVERLAID OF GLUCOSE
EXCURSION IN INDIVIDUALS WITH
DIABETES.
WHAT KEVIN DEMONSTRATED
FOLLOWING TWO WEEKS OF
CONTINUOUS GLUCOSE MONITORING
PRIOR TO ETI AND THEN IN THE
SEVERAL WEEKS FOLLOWING ETI
GLUCOSE EXCURSION IMPROVED WITH
THERAPY.
WASHINGTON UNIVERSITY GROUP IN A
RETROSPECTIVE ANALYSIS OF
CLINICALLY AVAILABLE DATA IN 139
INDIVIDUALS, NOT TREATED WITH
ETI FOR APPROXIMATELY 12 MONTHS
DEMONSTRATED NOT SURPRISINGLY
INCREASES IN WEIGHT, BMI,
INCREASING RATES OF OVERWEIGHT
AND TO LESSER EXTENT OBESITY.
HIGHER RATES OF HYPERTENSION.
IN SUBSET OF 20 OR SO
INDIVIDUALS WITH DIABETES, THEY
DEMONSTRATED INCREASES IN
CHOLESTEROL.
PUTNAM LOOKED AT IMPACT OF
IVACAFTOR, AT THE RADIUS AND
TIBIA.
AND THIS TOOL GIVES CORTICAL AND
TRABECULAR VOLUME, CORTICAL AREA
AS WELL AS CORTICAL THICKNESS,
MUCH MORE INFORMATIVE WITH
RESPECT TO BONE FRAGILITY THAN
TRADITIONAL DEXA.
HERE IS AN EXAMPLE OF AN
OTHERWISE HEALTHY FEMALE SHOWING
CORTICAL AND TRABECULAR BONE,
COMPARABLE AGE WITH CF, SMALLER
BONES, CORTICAL BONE IS LOWER,
FEWER TREBEKULAE.
TWO-YEAR CHANGES IN PARAMETERS,
AND DEMONSTRATING INCREASES IN
CORTICAL AREA AS WELL AS
CORTICAL THICKNESS.
PROMISE , WHICH PREVIOUS
PRESENTERS DISCUSSED, A
PROSPECTIVE STUDY TO EVALUATE
EFFECTS OF ETI ON MULTIPLE
OUTCOME, STUDY STARTED IN THE
FALL OF 2019 FOLLOWING FDA
APPROVAL, AND HERE INCLUDED IN
DATA I WILL SHOW ARE THOSE
SUBSET OF INDIVIDUALS AGE 12 AND
OLDER WHEN THEY WERE PRESCRIBED
ETI CLINICALLY.
I'M GOING TO FOCUS ON ENDOCRINE
SUBSTUDY, DATA AT 0, 12-18,
24-30 MONTHS, THAT COLLECTION IS
GOING ON NOW, AND THIS IS
EXTENDED OUT TO 54 MONTHS.
WE'RE OBTAINING THREE-OUR OGTT
AND DEXA FOR BONE AND BODY
COMPOSITION.
AND WE RECOGNIZE THAT BASED UPON
CLINICAL EXPERIENCE AND CASE
REPORTS THAT WE PROBABLY NEED A
LONGER TIME FRAME TO SEE CHANGES
AND SO THAT'S WHY WE HAVE GONE
TO 12 TO 18 MONTHS AND 24 TO 30
MONTHS VERSUS LOOKING AT ACUTE
CHANGES TO MODULATOR THERAPY.
I'LL SHOW HERE 12-18 MONTH DATA,
WHICH WE RECENTLY HAVE
AVAILABLE.
I'LL SHOW GLUCOSE TOLERANCE TEST
DATA AND EARLY PHASE INSULIN
SECRETION DATA.
BECAUSE MOST OF YOU IN THE
AUDIENCE HAVE NOT THOUGHT ABOUT
GLUCOSE EXCURSION ALL WALK YOU
THROUGH DATA.
ON THE LEFT-HAND PANEL IN GRAY
SHOWING THE NORMAL PLASMA
GLUCOSE IN RESPONSE TO A MEAL,
GLUCOSE PEAKS AT 30 MINUTES,
LOWER THAN BASELINE, GENERALLY
BY 2 HOURS.
AND THIS ARISES BECAUSE OF
INSULIN SECRETORY PROFILE ON THE
RIGHT, INSULIN PEAKS IN THE
FIRST 30 MINUTES, REFERRED TO AS
EARLY PHASE INSULIN SECRETION,
AND SECOND PHASE LESS ROBUST
INSULIN SECRETION PEAKING AT 60
MINUTES.
WITH NORMAL GLUCOSE TOLERANCE
WITH BLOOD GLUCOSE LESS THAN 155
AT ONE HOUR AND LESS THAN 140 AT
TWO HOURS YOU CAN SEE ONE-HOUR
GLUCOSE IS HIGH RELATIVE TO
OTHERWISE HEALTHY INDIVIDUAL
WITHOUT CF CAN DAMPENING OF
SECRETION ACCOMPANIED BY ROBUST
BUT DELAYED COMPENSATORY SECOND
PHASE SECRETION.
INDIVIDUALS WITH EARLY
TOLERANCE, PURPOSING SHOWS
DAMPENING OF EARLY FACE
SECRETION.
RED AND ORANGE IMPAIRED
TOLERANCE, EARLY PHASE INSULIN
SECRETION IS LEST, SECOND PHASE
IS ROBUST BUT DELAYED AND
GRADUAL DECLINE IN SECOND PHASE
SECRETION IS ASSOCIATED WITH
WORSEN OF CFRD.
>> FIVE-MINUTE WARNING.
>> INDIVIDUALS WITH NORMAL
TOLERANCE, FOUR WORSENED DURING
OF THE 12-18 MONTHS ETI.
23 WITH EARLY GLUCOSE
INTOLERANCE, FIVE WORSENED, ONE
IMPROVED.
AS WE GET TO WORSENING
TOLERANCE, SEEING GREATER
IMPROVEMENTS, 11 IMPROVED, THREE
CFRD PATIENTS IMPROVED.
THERE'S NORMAL VARIABILITY BUT
MANY HAVE APPRECIATED SUBSET OF
PATIENTS WHO IMPROVED GLUCOSE
TOLERANCE WITH ETI.
A LITTLE BIT MORE GRANULAR DATA
THE AREA UNDER THE CURVE FOR
GLUCOSE, SECRETORY RATES, NEW
CHANGES IN INSULIN SENSITIVITY
WITH ETI.
OTHER GLUCOSE PARAMETERS, I'LL
HIGHLIGHT SUBSET OF 50+
INDIVIDUALS WHO WERE NOT TREATED
WITH INSULIN DURING THE 12-18
MONTHS.
THERE WAS A DECREASE IN FASTING
GLUCOSE, 3 1/2 MILLIGRAMS PER
DECILITER, ETI MAY HAVE
FAVORABLE IMPACTS UPON GLUCOSE
BEYOND MEAL-RELATED INSULIN
SECRETION.
WE FOUND OUT ABOUT A QUARTER
PERCENT DECREASE IN HEMOGLOBIN
AI 1 D -- A1c, COMPARABLE FROM
SWITCHING INJECTION TO PUMP.
SWITCHING GEARS, CARDIOMETABOLIC
HEALTH, JESSICA ALVAREZ WILL
TALK ABOUT NUTRITION BODY
COMPOSITION AND BMI.
I'M FOCUSING ON 50 INDIVIDUALS
FROM PROMISE WHO HAD FASTING
LIPIDS, LDL LESS THAN 100 IS
CONSIDERED FAVORABLE FOR PEOPLE
WITH ESTABLISHED CARDIOVASCULAR
DISEASE, LEVELS LESS THAN 70 ARE
TARGETED.
AND HOPEFULLY YOU CAN APPRECIATE
MANY PATIENTS HAVE REALLY GOOD
LDL.
THERE WAS AN OVERALL INCREASE IN
LDL WITH ETI TREATMENT, BUT THAT
WAS LARGELY EXPLAINED BY CHANGES
IN BMI.
IN CONTRAST HDL ALSO INCREASED
OVER THAT TIME FRAME, BUT WAS
NOT ASSOCIATED WITH BMI AND THAT
INCREASE PERSISTED AFTER
ADJUSTMENT FOR BMI.
I THINK THIS RAISES SOME
QUESTIONS, INCLUDING ARE THE LOW
CHOLESTEROL THAT WE
TRADITIONALLY SEE IN CF RELATED
TO MALNUTRITION AND
MALABSORPTION, D DOES ETI
IMPROVE, AND ARE WE GOING TO SEE
EMERGENCE OF DYSLIPIDEMIA IN
YOUTH AND ADULTS IN CF.
THE FOUNDATION RECOMMENDS
LUMBAR SPINE AND HIP DEXA, WE
OBTAINED WHOLE BODY DEXA.
LESS THAN NEGATIVE 2 BONE
DENSITY.
WHAT I WANTED TO HIGHLIGHT ON
AVERAGE NO DIFFERENCE AT ANY OF
THE SKELETAL SITES WAS
IDENTIFIED 12 TO 18 MONTHS OF
ETI BUT I WANT TO ACKNOWLEDGE
THERE ARE A GOOD NUMBER OF
PEOPLE WHO HAVE LOW HIP DEXA,
MAKING ME CONCERNED ABOUT
INCREASED RISK FOR FRAGILITY
FRACTURE AT THE HIP WITH AGE.
WE'RE SEEING DECREASES IN Z
SCORES, SURPRISINGLY WITH 12 TO
18 MONTHS OF ETI THERAPY, AND
THAT WAS CONFIRMED WITH HIP,
ALSO SEEING THESE SUBTLE
DECREASES IN Z SCORES, I HAVE
NOTIONS OF WHY, BEYOND THE SCOPE
OF THIS CONVERSATION.
IN THIS EXCITING TIME, WE NEED
TO REASSESS WELL ESTABLISHED
COMORBIDITIES AND CONCERN
OURSELVES WITH POTENTIAL MASK OF
NEW CONDITIONS, RESPOND TO
CHANGING PHENOTYPES AND
SCREENING AND MANAGE
ACCORDINGLY.
MODULATOR THERAPY MAY IMPACT
CFRD RISK, MAY IMPACT
CARDIOMETABOLIC RISK, MAY NEED
TO RECONSIDER MANAGEMENT
INCLUDING USE OF TYPE 2 DIABETES
WITH MEDICATIONS, NUTRITIONAL
CHANGES, AND THEN CONSIDER A
SCREENING FOR COMPLICATIONS AND
WE MAY NEED TO BE ADDRESSING
MORE AGGRESSIVELY HYPERTENSION,
DYSLIPIDEMIA, OBESITY.
ALSO THE IMPACT OF MODULATOR
THERAPY ON BONE HEALTH AND RISK
OF FRACTURE WITH INCREASING AGE
IN OUR POPULATION.
WITH THAT I WOULD LIKE TO THANK
MY COLLABORATORS AND AGAIN THE
CF FOUNDATION AND NIH FOR THEIR
SUPPORT.
I'M SUPPOSED TO INTRODUCE
JESSICA ALVAREZ TALKING ABOUT
BMI AND BODY COMPOSITION.
>> THANK YOU, DR. KELLY.
WHILE SLIDES ARE COMING UP, I'LL
END WITH WHERE I THINK WE SHOULD
GO FOR NUTRITION RESEARCH IN
CYSTIC FIBROSIS.
I HAVE NO CONFLICT OF INTEREST
OR DISCLOSURES RELATED TO THIS
PRESENTATION.
WHAT ARE OUR KNOWLEDGE GAPS?
I'LL SPEAK TO EACH OF THESE BUT
TO START HOW DO WE DETERMINE
OPTIMAL NUTRITION STATUS FOR
HEALTH AND LONGEVITY FOR PEOPLE
WITH CF?
KEY HERE IS LONGEVITY, RIGHT?
WHAT IS THE OPTIMAL DIET FOR
PEOPLE WITH CYSTIC FIBROSIS?
I'M A DIETITIAN SO I LOVE FOOD.
AND THAT'S WHAT I LIKE TO
CONCENTRATE ON.
WHAT A LONG-TERM EFFECTS OF
MODULATOR THERAPY ON NUTRITION
STATUS.
NEXT SLIDE.
SEMINAL STUDIES SHOWS BETTER
NUTRITION STATUS AS DETERMINED
BY HEIGHT AND WEIGHT AND BMI IN
EARLY LIFE PREDICTS IMPROVED
SURVIVAL AND CLINICAL OUTCOMES.
WE SEE SURVIVAL CURVES SHOWING
HIGHER WEIGHT PERCENTILE AT 4
YEARS OF AGE WAS ASSOCIATED WITH
SURVIVAL AT 18 YEARS OF AGE.
NEXT SLIDE.
AND THIS LINK BETWEEN BMI AND
HEIGHT AND WEIGHT PARAMETERS AND
CLINICAL OUTCOMES HAS GUIDED
MANAGEMENT TO DATE.
THIS HAS BEEN THE
RECOMMENDATIONS HAVE BEEN A HIGH
CALORIE HIGH FAT DIET WITH
APPROPRIATE PANCREATIC ENZYMES,
SALT SUPPLEMENTATION, FAT
SOLUBLE VITAMIN SUPPLEMENTATION.
TO MEET MINIMUM BMI GOALS OF
50th PERCENTILE FOR CHILDREN,
22 AND 23 FOR MEN AND WOMEN.
THIS DIET QUITE OFTEN TRANSLATED
TO ONE WHERE NO CALORIE IS A BAD
CALORIE, AND YOU MIGHT SEE THIS
OR HEAR THIS REFERRED TO AS THE
LEGACY CF DIET.
WE KNOW THINGS ARE STARTING TO
CHANGE AND PEOPLE ARE STARTING
TO MAKE RECOMMENDATIONS ON
IMPROVING DIET QUALITY IN THIS
ASPECT.
NEXT SLIDE.
BUT HISTORICAL PLAN MADE SENSE.
SO LOOKING AT OLDER CYSTIC
FIBROSIS PATIENT REGISTRY
REPORTS YOU COULD ALWAYS SEE
THIS POSITIVE RELATIONSHIP
BETWEEN BODY MASS INDEX,
PERCENTILE AND LUNGS FUNCTION IN
CHILDREN FROM 2016.
NEXT SLIDE.
BUT WHEN WE COMPARE THE 2016
GRAPH ON THE LEFT-HAND SIDE TO
THE LATEST FROM THE YEAR 2020,
THE RELATIONSHIP BETWEEN BMI AND
LUNG FUNCTION STARTS TO LOOK
PRETTY DIFFERENT.
THIS HASN'T BEEN SCIENTIFICALLY
TESTED, I HAVEN'T DONE
STATISTICAL ANALYSIS BUT JUST
LOOKING AT THESE TWO HERE, IT
MAKES ME WONDER IF WE'RE SEEING
ALMOST IN THIS POST MODULATOR
ERA UNCOUPLING OF BMI FROM LUNG
FUNCTION AT LEAST IN CHILDREN AT
HIGHER PERCENTILES.
NEXT SLIDE.
AND ADULTS, THIS SLOPE BETWEEN
LUNGS FUNCTION AND BMI REMAINS,
WE CAN SEE THAT THERE.
NEXT SLIDE.
BUT STUDIES HAVE LOOKED MORE
RIGOROUSLY AT THIS RELATIONSHIP
TO SEE WHAT THAT EXTENT OF THE
RELATIONSHIP IS.
AND THEY ARE INDEED POSITIVELY
CORRELATED BUT A LOT OF STUDIES
SHOW THAT RELATIONSHIP ONLY
EXISTS AT A CERTAIN POINT.
SO SOME STUDIES LISTED HERE ON
THE RIGHT-HAND SIDE PUBLISHED
THRESHOLDS BEYOND WHICH
RELATIONSHIP BETWEEN BMI AND
LUNGS FUNCTION SEEMED TO BE
BLUNTED, RANGING BETWEEN 23 TO
29, BUT WHAT I'M SHOWING IS ONE
OF THE MOST RECENT STUDIES OUT
OF MINNESOTA SUGGESTING A
PLATEAU IN THAT RELATIONSHIP
BETWEEN BMI AND LUNG FUNCTION AT
ABOVE -- RIGHT AROUND 28 OR 29
KILOGRAMS PER METER SQUARED.
SO, AGAIN, THESE STUDIES SUGGEST
THAT TO A CERTAIN POINT
INCREASING BMI MAY NOT IMPROVE
LUNGS FUNCTION, AT LEAST AT THE
POPULATION LEVEL.
NEXT SLIDE.
ALMOST IN CONTRAST TO THAT
MESSAGE, A RECENTLY PUBLISHED
META-ANALYSIS OUT OF HUNGRY
SUGGESTED BETTER LUNGS FUNCTION
COMPARED TO THOSE WHO WERE
NORMAL WEIGHT.
HOWEVER, I WILL SAY THIS WAS
ONLY BASED ON CATEGORIES OF BMI
AND NOT AS A CONTINUOUS FUNCTION
LIKE I SHOWED IN THE SLIDE
EARLIER.
SO, A THRESHOLD WASN'T
DESCRIBED, AND YOU CAN SEE THAT
THE VARIABILITY OF THE
RELATIONSHIP, IT'S MUCH WIDER
WHEN THEY MOVED FROM LOOKING AT
NORMAL WEIGHT VERSUS OVERWEIGHT
TO LOOKING AT NORMAL WEIGHT
VERSUS OBESITY.
ANOTHER THING TO REMEMBER IF
YOU'RE READING THIS IS THAT THIS
META-ANALYSIS INCLUDED STUDIES
PUBLISHED BEFORE NOVEMBER 2020.
SO THE STUDIES ARE OLDER, AND
MORE HEAVILY WEIGHED BY THE
PRE-HIGHLY EFFECTIVE MODULATOR
DATA.
NEXT SLIDE.
SO, A BIG LIMITATION OF THE
STUDIES I'VE HIGHLIGHTED IS THAT
BMI DOESN'T PROVIDE ANY
INFORMATION ABOUT BODY
COMPOSITION.
IT'S A GREAT TOOL FOR SCREENING
AND IDENTIFYING PEOPLE AT THE
EXTREME ENDS OF MALNUTRITION AND
OVERWEIGHT, BUT IT DOESN'T
DISTINGUISH BETWEEN FAT MASS OR
MUSCLE AND FAT-FREE MASS, OR FAT
MASS OR FAT-FREE MASS.
WE HAVE MUSCLE, BONE, CONNECTIVE
TISSUE AND ORGANS WE CAN LOOK
AT.
WHAT WE'RE MOST CONCERNED ABOUT
WHEN THINKING ABOUT HEALTH AND
LONGEVITY IN CF AND OTHER
DISEASE STATES IS THE
PRESERVATION OF FAT-FREE MASS,
PRESERVATION OF BONE AND MUSCLE.
NEXT SLIDE.
ON A POSITIVE NOTE BMI IS A
USEFUL SURROGATE FOR FAT-FREE
MASS, BUT DOES CORRELATE WITH
FAT MASS.
AND WHEN WE COMPARE FAT-FREE
MASS VERSUS FAT MASS VERSUS BODY
MASS INDEX TO CLINICAL OUTCOMES
FAT-FREE MOST OFTEN PERFORMS
BETTER.
STUDIES IN CF HAVE SHOWN
FAT-FREE OR LEAN MASS, I USE
THOSE WORDS INTERCHANGEABLY, IS
A STRONGER CORRELATE OF LUNG
FUNCTION COMPARED TO BMI,
COMPARED TO FAT MASS.
SEVERAL STUDIES HAVE SHOWN FOR
THE LAST 20 YEARS THAT BMI HAS A
LOW SENSITIVITY FOR DETECTING
FAT-FREE MASS IN PEOPLE WITH CF
ACROSS ALL AGES.
AND THIS HASN'T BEEN STUDIED IN
CF YET BUT IN OTHER PULMONARY
DISEASES SUCH AS COPD FAT-FREE
MASS IS STRONGER PREDICTOR OF
MORTALITY.
NEXT SLIDE.
SO, LOOKING AT BODY COMPOSITION
AND RELATIONSHIPS WITH LUNG
FUNCTION AND CLINICAL OUTCOMES,
HERE IS A STUDY WE PUBLISHED IN
2016 THAT SHOWED THE EXPECTED
POSITIVE RELATIONSHIP BETWEEN
BMI AND LUNG FUNCTION.
WE ALSO FOUND FAT-FREE MASS,
LOOKED AT THAT ALSO AND FOUND
SIMILAR POSITIVE RELATIONSHIP.
BUT VERY SURPRISING FINDING
THERE WAS INVERSE RELATIONSHIP
BETWEEN OUR MEASURES OF ADIPOSE
TISSUES, PERCENT BODY FAT, EVEN
LOOKING AT FAT MASS ON ITS OWN,
IT WAS INVERSELY ASSOCIATED WITH
LUNG FUNCTION.
HIGHER BODY FAT, LOWER LUNG
FUNCTION.
THIS STARTED TO GIVE MORE DETAIL
ABOUT LUNG FUNCTION AND STUFF WE
COULDN'T SEE WHEN JUST LOOKING
AT BODY MASS INDEX.
NEXT SLIDE.
AND THIS JUST SHOWS A MORE
RECENT COHORT STUDY LED BY DR.
PUTNAM AT HARVARD, SUPPORTED
POSITIVE RELATIONSHIP WITH LEAN
MASS, INVERSE RELATIONSHIP WITH
FAT MASS INDICES.
NEXT SLIDE.
WE SPENT TIME FOCUSING ON MUSCLE
MASS OR MUSCLE SIZE, SOMETIMES
MUSCLE FUNCTION CAN BE
OVERLOOKED.
MY LAB AND OTHERS HAVE LOOKED AT
HOW HAND GRIP STRENGTH, MEASURE
OF MUSCLE FUNCTION, CAN
CORRELATE CAN DEXA-DERIVED
MEASURES OF BODY COMPOSITION.
ON THE LEFT-HAND PANEL IS WE
DIDN'T FIND -- THIS WAS AN
ABSTRACT WE, NO RELATIONSHIP
BETWEEN HAND GRIP STRENGTH AND
BMI BUT STRONG RELATIONSHIP WITH
STRENGTH AND LEAN MASS AND TOTAL
BONE MARROW DENSITY.
AND SIMILAR TO WHAT SOME OTHER
FINDINGS WE FOUND INVERSE
RELATIONSHIP BETWEEN HAND GRIP
STRENGTH AND PERCENT BODY FAT.
NEXT SLIDE.
SO IN KEEPING WITH THE THEME BMI
DOESN'T TELL ALL, WE'VE LOOKED
AT NORMAL WEIGHT OBESITY IN
ADULTS WITH CF, BASICALLY HAVING
A NORMAL WEIGHT BMI IN NUMBERS
BUT DISPROPORTIONATELY HIGH
PERCENTAGE BODY FAT, ALMOST A
THIRD OF OUR GROUP THAT WE
STUDIED HERE HAD NORMAL WEIGHT
OBESITY.
WHEN WE LOOKED AT GROUP
DIFFERENCES HOWEVER IN LUNG
FUNCTION BETWEEN BMI CATEGORIES
IT WAS THE NORMAL WEIGHT OBESE
GROUP, THIS PINK BAR, THAT HAD
THE LOWEST LUNG FUNCTION, ALSO
NOT COINCIDENTALLY WAS ALSO THE
GROUP THAT HAD THE LOWEST
FAT-FREE MASS, LOWEST MUSCLE.
NEXT SLIDE.
>> FIVE-MINUTE WARNING.
>> OKAY.
IN A MORE RECENT STUDY COMPARED
BODY COMPOSITION TO HEALTHY
CONTROLS USING DEXA.
IN THE STUDY I'M SHOWING HERE WE
HAD GROUPS WELL MATCHED FOR BMI
AND FAT MASS AND LEAN MASS BUT
SOMETHING PRETTY SHOCKING TO US
WAS A MUCH HIGHER VISCERAL
ADIPOSE TISSUE, FAT IN THE
ORGANS, WHEN THE VISCERAL AREA
IN OUR ADULTS CAN CYSTIC
FIBROSIS COMPARED TO CONTROLS.
NEXT SLIDE.
AND THEN DATA THAT DR. KELLY
SHOWED US, WE FOUND A POSITIVE
RELATIONSHIP BETWEEN VISCERAL
ADIPOSE TISSUE IN SAME SUBJECTS,
MEASURES OF FASTING GLUCOSE.
NEXT SLIDE.
WHAT ABOUT DIET?
IN THE SAME COHORT OF ADULTS WE
DIDN'T FIND ANY DIFFERENCES
AFTER WE ADJUSTED FOR CALORIE IN
OVERALL MACRONUTRIENTS,
CARBOHYDRATES, FAT, PROTEIN.
BUT WHEN WE DUG DEEPER AND
LOOKED AT DIET QUALITY,
INDICATORS OF QUALITY, WE FOUND
OVERALL MEASURES OF DIET QUALITY
WERE WORSE IN OUR ADULTS WITH CF
COMPARED TO OUR HEALTHY
CONTROLS.
AND THAT INCLUDED ADDED SUGAR
INTAKE, GLYCEMIC LOAD, FIBER AND
FATTY INTAKE, LOOKED AT HEALTHY
EATING INDEX, LOWER IN CF
COMPARED TO CONTROLS.
NEXT SLIDE.
WE'VE ALSO LOOKED AT
RELATIONSHIP BETWEEN DIET AND
BODY COMPOSITION, ADDED SUGAR
INTAKE WAS ASSOCIATED,
HIGHLIGHTING WE NEED TO FOCUS ON
NUTRITION, SHIFTING FOCUS TO
NUTRITION ASSESSMENT TOWARDS
BODY COMPOSITION AND DIET
QUALITY AS OPPOSED TO HEIGHT AND
WEIGHT AND TOTAL CALORIE INTAKE.
AND AS DR. KELLY SHOWED THERE'S
GOOD BIT OF VARIABILITY IN
EFFECTS OF MODULATORS ON
ENDOCRINE FUNCTION, SO WE NEED
TO START THINKING ABOUT OTHER
MODIFIERS, OTHER POTENTIAL
MODIFIERS TO CF DIABETES RISK.
DIET QUALITY COULD WELL BE ONE
OF THEM.
NEXT SLIDE.
AS DR. KELLY SHOWED US,
MODULATORS ARE EFFECTIVE AT
INCREASING BMI SOME MECHANISMS
OF WEIGHT GAIN PROPOSED ARE
DECREASED MALABSORPTION,
DECREASED GUT INFLAMMATION,
DECREASED ENERGY EXPENDITURE.
IS IT WEIGHT GAIN, FAT, MUSCLE
OR BOTH.
>> ONE-MINUTE WARNING.
>> THIS IS JUST A STUDY FROM
KING OUT OF AUSTRALIA SHOWING
CHANGES OVER 28 DAYS IN FAT-FREE
MASS, NOT FAT MOSS FOLLOWING
IVACAFTOR USE, BY SIX MONTHS 64%
OF THE TOTAL WEIGHT GAIN WAS FAT
MASS, AND THEN BY 2 1/2 YEARS NO
FURTHER CHANGES IN BODY
COMPOSITION.
I'LL SKIP OVER THE NEXT SLIDE
WHICH SHOWS SIMILAR FINDINGS OF
INCREASED FAT MASS BUT NOT
FAT-FREE MASS IN ADULTS
FOLLOWING IVACAFTOR US A.
I'M GOING TO END HERE WITH
READDRESSING OUR CF NUTRITION
KNOWLEDGE GAPS.
WE KNOW MAINTENANCE OF ADEQUATE
NUTRITION IS CRITICAL FOR CF.
HOW DO WE BEST ASSESS NUTRITION
NOW IN THIS POST-MODULATOR ERA?
BMI REMAINS A USEFUL SCREENING
TOOL, CAN LONGITUDINAL BODY
COMPOSITION FAT DISTRIBUTION ADD
FURTHER INSIGHT INTO PROGRESSION
OF CF HEALTH AND DISEASE NOW?
GIVEN IMPROVEMENTS IN LUNG
FUNCTION POST MOD MODULATOR
DOES IT REMAIN A GOOD ENDPOINT
FOR NUTRITION STUDIES?
MOST NUTRITION RECOMMENDATIONS
FOR ENERGY EXPENDITURE, DIETARY
NEEDS AND TARGET NUTRITION GOALS
COME FROM WONDERFUL RESEARCH,
ABSOLUTELY WONDERFUL RESEARCH
DONE BEFORE CFTR MODULATOR
THERAPY WAS AVAILABLE SO NOW
THERE'S A HUGE NEED TO DETERMINE
THESE NEW BASELINE NUTRITION
STATUS, AND IN TERMS OF DIET
WHAT ARE MACRO AND MICRO
NUTRIENT NEEDS NOW, HOW DO THESE
DIFFER WITH COMORBIDITIES SUCH
AS CF-RELATED DIABETES?
AND FINALLY HOW DO MODULATORS
AFFECT NUTRITION FOR PEOPLE WITH
CF, IS OVERWEIGHT OBESITY A
CONCERN?
WHAT ARE LONG-TERM EFFECTS OF
MODULATORS ON BODY COMPOSITION
AND CARDIOMETABOLIC RISK.
BOTTOM LINE NEW STUDIES ARE
NEEDED TO BETTER DEFINE OPTIMAL
NUTRITION STATUS FOR HEALTH AND
LONGEVITY IN PEOPLE WITH CF.
SO I WILL END WITH
ACKNOWLEDGMENTS.
NEXT SLIDE.
WONDERFUL STUDY TEAM AND GEORGIA
CF CENTER, THAT'S BEEN
SUPPORTIVE MUCH NUTRITION
RESEARCH AS WELL AS MY MANY
COLLABORATORS OUTSIDE EMORY WHO
I'VE LOVED WORKING WITH.
I THINK THAT'S IT.
WE WILL MOVE ON TO THE Q&A
SESSION.
>> THANK YOU, JESSICA, FOR THE
TALK.
THANK YOU TO ALL THE SPEAKERS IN
THIS SESSION.
I THINK YOU'LL NOTICE AS WE MOVE
FORWARD THAT UNLIKE THE FIRST
SESSION THERE'S DISPARATE TALKS
THAT COVER BROAD CATEGORIES IN
EACH OF THESE SESSIONS AS WE
MOVE FORWARD.
WE'LL START WITH SOME QUESTIONS
THAT HOPEFULLY ALL OF THE
SPEAKERS CAN ADDRESS AND WE HAVE
SPECIFIC QUESTIONS FOR EACH OF
THE INDIVIDUAL SPEAKERS, AS WELL
AS DIRECTING QUESTIONS TO
SPEAKERS, SOME BEING ANSWERED
IN THE CHAT.
FIRST QUESTION, BIG QUESTIONS
ACROSS THE BOARD, ANYONE WHO
WANTS TO ANSWER IT, DOES ANYONE
THINK THAT WE WILL BE ABLE TO
REVERSE BRONCHIECTASIS,
REMODELING INTO A MORE
FUNCTIONAL AIRWAY?
FRANK OR ESZTER, PRADEEP?
>> WE HAVEN'T SEEN ANY TENDENCY
OF THEM WANTING TO DO THAT.
WE HAVE NOT -- WE DON'T SEE
EVIDENCE OF PLASTICITY.
THEY SEEMED TO BE SO
EPIGENETICALLY FIXED.
I THINK THAT'S GOING TO BE A
CHALLENGE.
>> CONTEXT OF AIR-LIQUID
INTERFACE CULTURE
DIFFERENTIATION WE'VE DONE
STUDIES WHERE WE'VE MODULATED
DEVELOPMENTAL SIGNALING PATHWAYS
LIKE NOTCH AND WNT SIGNALING IN
CF CULTURES WHICH HAVE ALLOWED
THEM TO FORM A MORE NORMAL
EPITHELIUM AS LEAST IN TERMS OF
COMPOSITION.
BUT WHETHER THAT IS SOMETHING
YOU CAN, LIKE FRANK SAID,
PROGRAM INTO PROGENITOR
POPULATION, THAT'S THE
CHALLENGE.
>> I DON'T KNOW IF IN THE
PROMISE STUDY YOU DID -- WE'VE
BEEN LOOKING AT CAT SCANS LIKE
THE IRISH COHORT.
MY UNDERSTANDING IS THE CURRENT
UNDERSTANDING IS THAT FOLLOWING
CAT SCANS WE DON'T SEE
BRONCHIECTASIS RESOLVE, IS THAT
CORRECT?
>> THANKS FOR THE QUESTION.
UNFORTUNATELY PROMISE DOES NOT
HAVE AN IMAGING ARM, SO I DON'T
THINK WE'LL BE ABLE TO ANSWER
THAT ON A LARGE SCALE WITH
PROMISE.
I THINK YOU'RE RIDE -- RIGHT
THAT'S THE DOGMA BRONCHIECTASIS
CAN BE CONSIDERED IRREVERSIBLE
LESION.
I DON'T KNOW IF IT'S TRUE.
WE NEED TO KNOW THAT.
THAT'S A KEY QUESTION THAT MAY
DIFFER DEPENDING ON WHAT THE
PATHOGENS ARE PRESENT OR ABSENT,
WE NEED TO KNOW THAT.
>> ANOTHER UNIFIED QUESTION,
OBVIOUSLY, CLEARS THE LUNGS,
SYSTEMIC METABOLISM, THESE
THINGS INTERRELATE.
AS THINGS ARE CHANGING WITH
MODULATORS THIS MAY BE MORE
ABOUT THE GENERAL LITERATURE,
INFLAMMATION, METABOLISM, WHAT
DO WE THINK IS HAPPENING IN
TERMS OF MEDIATORS IN THE
PLASMA, METABOLITES, GLUCOSE
LEVELS, LUNG INFLAMMATION,
ABILITY TO REPAIR, DIFFERENT
KINDS OF INFECTION, DO WE THINK
INFECTIONS IN THE LUNG AND
INFLAMMATION IN THE LUNG IS
GOING TO AFFECT METABOLICS
SYNDROME, METABOLISM?
BIG QUESTION.
ANY OF YOU CAN ANSWER.
>> I'LL START WITH -- I CAN'T
SPEAK TO INFECTION OR EPITHELIA
BUT OLDER STUDIES BY STEVE
FRIEDMAN AND OTHERS AT HARVARD
LOOKING AT ESSENTIAL FATTY ACID
DEFICIENCIES AND THEIR
RELATIONSHIP TO HELP IN CF, DONE
YEARS AGO, AND ANOTHER TOPIC WE
NEED TO REVISIT AS MALABSORPTION
IMPROVED WITH HIGHLY EFFECTIVE
MODULATOR THERAPY OVERALL.
>> ANY OTHER THOUGHTS, GLUCOSE
LEVELS, CHANGING HOW THE LUNG
FUNCTION --
>> I THINK IT'S A GREAT
QUESTION.
YOU KNOW, AS WE WERE PROBING THE
DATA FROM PROMISE, ONE OF THE
QUESTIONS THAT WE WERE TRYING TO
ANSWER AT LEAST IN THE 12-18
MONTH DATA WERE IMPROVEMENTS IN
PULMONARY FUNCTION ASSOCIATED
WITH BETTER IMPROVEMENTS IN
GLUCOSE EXCURSION, THAT DID NOT
PAN OUT.
WE HAVE NOT YET LOOKED AT EARLY
INSULIN SECRETION, WHICH I THINK
MAY BE QUITE RELEVANT AND
HAVEN'T PAIRED DATA WITH
SYSTEMIC INFLAMMATORY MARKERS
BUT GIVEN INFLAMMATION UNDERLIES
AT LEAST PARTLY SOME OF THE BETA
CELL DYSFUNCTION AS THAT
INFLAMMATION IMPROVES
SYSTEMICALLY WILL WE ALSO SEE
THAT AT THE LEVEL OF THE
PANCREAS, CERTAINLY IN PEOPLE
THERE HAVE BEEN SUBSET OF PEOPLE
WHO HAVE SOME RESIDUAL
PANCREATIC EXOCRINE FUNCTION
THAT SEEM TO HAVE IMPROVEMENT
WITH MODULATOR THERAPY.
AND THAT BEGS THE QUESTION,
COULD THAT SORT OF STALLING OF
THAT INFLAMMATION THERE ALSO
FLOW OVER TO IMPROVEMENTS IN
BETA CELL FUNCTION, SO I THINK
IT'S A BIG QUESTION THAT NEEDS
TO BE ANSWERED BUT WE DON'T HAVE
THE DATA YET TO SUPPORT EITHER
WAY.
>> ONE POINT TO ADD, THE WAY THE
PROMISE STUDY WAS DESIGNED,
EVENTUALLY ALL THESE PARAMETERS
WILL BE ABLE TO BE
CROSS-CORRELATED TO LOOK AT LUNG
INFLAMMATION, LUNG INFECTION,
METABOLIC PARAMETERS, GROWTH
PARAMETERS, G.I. PARAMETERS, SO
HOPEFULLY THAT WILL AT LEAST
START GETTING TO THE ASSOCIATION
LEVEL IN ANSWER TO YOUR
QUESTION.
>> THAT'S GREAT.
GLAD WE HAVE ALL THAT DATA.
SOME SPECIFIC QUESTIONS, FRANK,
I'M GOING TO SEE IF I GET THESE
QUESTIONS RIGHT.
IF THE CF VARIANTS HAVE LIMITED
DIFFERENTIATION POTENTIATION
ARE THEY TISSUE STEM CELLS?
AND CAN YOU FORCE THEM TO MAKE
CILIATED CELLS FOR EXAMPLE WITH
NOTCH INHIBITORS?
>> THE LAST PART, THEY ARE STEM
CELLS BY ALL CRITERIA.
THEY ARE P63 POSITIVE AS IS THE
NORMAL DISTAL AIRWAY STEM CELL.
AND YOU CAN SEE THEM IN VIVO.
YOU KNOW, SUBTENDING MET PLASTIC
LESIONS IN THE CF LUNG.
SO, OUR SENSE RIGHT NOW IS THEY
HAVE ALL THE PROPERTIES OF
FORMAL STEM CELL WITH HIGH
CLONOGENICICITY TO BOOT.
WHETHER WE CAN TWISTER THEM, USE
VARIOUS PATHWAY INHIBITORS TO
GET THEM TO BEHAVE IN A MORE
NORMAL FASHION WE DON'T HAVE ANY
INFORMATION ON THAT YET.
IT'S REALLY INTERESTING.
>> AND THEN ALSO HOW LONG HAVE
WE OBSERVED ABNORMAL CF-SPECIFIC
STEM CELL VARIANTS IN A NORMAL
ENVIRONMENT, IS THERE INDICATION
PERSISTENT GROWTH CAN REPROGRAM
THEM, BACK TO BRONCHIECTASIS
QUESTIONS, NORMAL STEM CELL
VARIANTS COMPETITIVE ADVANTAGE?
>> WE'VE GROWN THEM FOR I THINK
PASSAGE 25 WHICH IS ALMOST A
YEAR.
AND THEY DON'T CHANGE DURING
THAT TIME.
THEY ARE ALSO GENOMICALLY STABLE
DURING THAT TIME, DON'T SEEM TO
CARE ABOUT ANYTHING.
AND SO WE JUST DON'T SEE ANY
PLASTICITY.
THEY SEEM TO BE ABSOLUTELY
FIXED.
WE DON'T SEE THEM DIFFERENT FROM
THE ONES WE CAN ISOLATE FROM
21-WEEK-OLD FETAL LUNGS.
I THINK THEY ARE JUST PART OF
OUR INNATE IMMUNE SYSTEM.
AND FOR GOD KNOWS WHAT REASON,
THEY STAY HIGH IN ALL THESE
CHRONIC INFLAMMATORY DISEASES.
AND I THINK, YOU KNOW, AT LEAST
THE DRUG DEVELOPMENT WE'RE DOING
SOMEHOW HAS HIT ON SOME ASPECT
OF WHY THEY STAY PRESENT.
SO WE'RE VERY INTERESTED IN THE
ONES WE SEE FOR CYSTIC FIBROSIS
ARE THE SAME AS -- HAVE THE SAME
SENSITIVITY TOWARDS THE VARIANT
IN IDIOPATHIC PULMONARY FIBROSIS
SO THERE'S SOMETHING ABOUT THESE
VARIANTS THAT STAY HIGH THAT
RENDERS THEM VULNERABLE, YOU
KNOW, THEY SHOULDN'T BE DOING
THAT, THEY SHOULD BE
DISAPPEARING AFTER INFECTION.
>> THANK YOU.
SIMILAR SORT OF IDEA ABOUT CAN
WE CHANGE THINGS, CAN WE
INTERVENE FOR ESZTER, GREAT
TALK, AS YOU KNOW WE FOUND THE
SINUS DISEASE IMPROVED SUBSTANCE
BUT WE COULDN'T REVERSE ANOSMIA
IN ADULTS.
HAVE YOU LOOKED AT HOW NASAL
EPITHELIUM COMPARES TO ADULTS,
ARE THERE CLUES TO PREVENT IF WE
ADMINISTER HEMP EARLIER?
>> THAT'S THE CRITICAL THING.
I HAVEN'T DONE THE EXPERIMENT.
WE'VE ONLY LOOKED AT THE ONE
ADULT POPULATION, BUT THE IDEA
HERE IS THE TIMING AND WHETHER
THERE IS IRREVERSIBLE DAMAGE IN
A TERMINALLY DIFFERENTIATED CELL
TYPE THAT YOU CAN REPOPULATE
POTENTIALLY.
OR EVEN THE EXTENT, WHICH WE'VE
TUSHED ON DURING THIS MEETING A
COUPLE WAYS, WHICH WE STILL
DON'T 100% KNOW IN THE DIFFERENT
COMPARTMENTS AND WHAT IS THE
THRESHOLD LEVEL OF CORRECTION
THAT YOU NEED IN DIFFERENT
TISSUES TO GET A PHENOTYPIC
CHANGE.
>> JESSICA, DO YOU WANT TO TAKE
OVER FOR THE NEXT FEW?
>> THIS IS A QUESTION FOR
PRADEEP.
ANY THOUGHTS TO WHY ETI REDUCES
ONLY CF PATHOGENS AND NOT OTHER
BACTERIA IN THE AIRWAY?
AND THERE ARE FOLLOW-UP
QUESTIONS.
RELATED TO THAT QUESTION, DOES
THE ENVIRONMENT CHANGE DUE TO
ETI TREATMENT THAT NOW SELECTS
AGAINST PATHOGENS?
ARE PATIENTS NOT BEING TREATED
WITH ANTIBIOTICS AS OFTEN SINCE
SOME CLINICAL PARAMETERS ARE
IMPROVING?
>> I THINK WE DON'T KNOW THE
ANSWER AS TO WHY CF PATHOGENS GO
DOWN AND THE OTHER BACTERIA IN
SPUTUM STAY THE SAME.
I THINK THE PREPONDERANCE OF
EVIDENCE FROM MY POINT OF VIEW
WOULD SUGGEST THAT MOST LIKELY
MECHANISM IS THAT THOSE OTHER AT
LEAST MOST OF THOSE OTHER
BACTERIA ARE CONTAMINANTS COMING
FROM THE ORAL PHARYNX.
THERE'S BEEN A FEW STUDIES THAT
LOOKED DIRECTLY IN LUNGS BY
DIRECT SAMPLING.
WE FIND CF PATHOGENS ARE
ABUNDANT, THE OTHER BACTERIA
PRESENT IN SPUTUM ARE EITHER
ABSENT OR MUCH LESS ABUNDANT.
I THINK WHAT'S PROBABLY
HAPPENING IS THAT ETI IS WORKING
IN THE LUNGS, THAT'S WHERE THE
LUNG PATHOGENS ARE.
THEY ARE GOING DOWN.
AS THAT SPUTUM SAMPLE COMES UP,
IT GETS ADMIXED WITH SALIVA AND
UPPER AIRWAY SECRETIONS THAT
HAVE HUGE CONCENTRATIONS OF ORAL
ANAEROBES, UP TO 10 TO THE
10th GENOME COPIES PER MIL.
IF YOU GOT A MIL OF SPUTUM
COMING UP, IT GETS CONTAMINATED
WITH 10% SALIVA, THAT WILL GIVE
A SIGNAL OF 10 TO THE EIGHTH, 10
TO THE SEVENTH, A BIG SIGNAL OF
ORAL ANAEROBES.
IT COULD BE WE CAN'T SEE THE
CHANGE BECAUSE THEY ARE DWARFED
BY CONTAMINANT SIGNAL.
EVERYTHING WE KNOW ABOUT
MECHANISM OF CORRECTORS AND
MODULATORS IS THEY SHOULD LIKELY
IMPROVE BROAD SPECTRUM
INDISCRIMINATE LUNG DEFENSES, SO
CLEARANCE REMOVES PARTICLES,
DOESN'T CARE THE SPECIES, IT'S
GOING TO REMOVE PHYSICALLY.
IMPROVED AIR WAY pH WILL
INCREASE ACTIVITY OF MICROBIALS
IN THE AIRWAY WITH BROAD
SPECTRUM ACTIVITY.
PUTTING THOSE IDEAS TOGETHER, I
THINK THE MOST LIKELY
EXPLANATION IS THOSE OTHER BUGS
DON'T CHANGE BECAUSE OF
CONTAMINANTS.
BECAUSE THEY ARE CONTAMINANTS.
AS FAR AS ANTIBIOTIC USE, I
DEFER TO OTHERS TO ANSWER THAT
MORE DEFINITIVELY, PRELIMINARY
DATA FROM THE PROMISE STUDY
SUGGESTS THERE IS A DECLINE IN
INHALED ANTIBIOTIC USE AT THE
SIX-MONTH TIME POINT.
SO IT COULD BE THAT THE, YOU
KNOW, THE CHANGES COULD BE
GREATER PERHAPS, IF ANTIBIOTIC
USE HAD CONTINUED, COULD BE
ANTIBIOTIC IS IMMATERIAL, WE
HAVE MODULATORS, DON'T KNOW THAT
QUESTION.
WE NEED A CONTROL STUDY TO
ANSWER THAT.
>> THANK YOU.
WE HAVE SOME MORE QUESTIONS FOR
YOU IF YOU'RE OKAY WITH THAT.
IT LOOKS LIKE THE DATA THAT WAS
PRESENTED IS AMONG PARTICIPANTS
WHO WERE STILL ABLE TO PRODUCE
SPUTUM AFTER STARTING ETI, CAN
THIS BE EXTRAPOLATED TO THOSE
WHO NO LONGER PRODUCE SPUTUM?
>> THE WISDOM WAS TO COME UP WAS
USE INDUCED SPUTUM, ALL SUBJECTS
GET INHALATION INDUCED SPUTUM
SAMPLES THROUGHOUT THE STUDY.
COVID PANDEMIC MESSED THAT UP
BECAUSE IT'S AN
AEROSOL-GENERATING PROCEDURE, WE
STARTED TO ACCEPT INDUCED AND
SPONTANEOUS SPUTUM LATER IN THE
STUDY.
IT'S A MIXTURE OF PEOPLE THAT --
MIXTURE OF SPUTUM SAMPLES THAT I
PRESENTED.
I THINK WE NEED TO KNOW THAT,
YEAH.
WE'VE CERTAINLY SEEN THE BAL
STUDIES, A PATIENT OR TWO, WHO
HAVE BECOME CLINICALLY
NON-PRODUCTIVE, SO CLINIC SAYS
THEY CAN'T GET ANY SPUTUM, WE GO
IN WITH A BRONCHOSCOPE AND FIND
CF PATHOGEN THAT PREEXISTED
BEFORE ETI, WE SEQUENCE THAT
PATHOGEN WE FIND IT'S THE SAME
STRAIN, SAME LINEAGE.
IT'S A CLONAL DESCENDANT OF THE
BUGS THAT PREEXISTED.
SO I THINK THAT THE IMPLI
QUAILINGS -- IMPLICATION OF THE
QUESTION IS CORRECT, PROBABLY A
NUMBER OF PEOPLE, SIGNIFICANT
PROPORTION THAT CAN'T PRODUCE
SPUTUM BUT CONTINUE TO HARBOR A
PATHOGEN IN THE LUNG, THE ONLY
WAY TO ANSWER IS BY DIRECT
SAMPLING.
>> I'M GOING TO MOVE TO
QUESTIONS FOR DR. KELLY.
FIRST ONE, WHAT CAUSES THAT
DELAY IN INSULIN SECRETION,
DELAY YET ROBUST -- DELAYED
SECRETION AMONG THOSE EVEN WITH
NORMAL GLUCOSE TOLERANCE.
>> GREAT QUESTION.
STUDIES ARE ACTIVELY GOING ON TO
TRY AND IDENTIFY WHY THERE IS
THAT LOSS OF EARLY PHASE INSULIN
SECRETION.
WE SEE THIS IN OTHER FORMS OF
DIABETES.
AND THERE'S INCREASING DATA
EMERGING IN TYPE 2 DIABETES THAT
EARLY PHASE IS PROBABLY QUITE
RELEVANT.
THAT EARLY PHASE REPRESENTS THE
GRANULES READILY AVAILABLE AT
BETA CELL MEMBRANE, MAY REFLECT
PROCESSING ISSUES WITH PRO
INSULIN NORMALLY GETTING TO
INSULIN BECAUSE IF WE LOOK AT
THE PRO INSULIN TO INSULIN RATIO
WHICH TELLS US ABOUT THAT
PROCESSING, THAT'S ABNORMAL EVEN
IN THE PATIENTS WITH CF, NORMAL
GLUCOSE TOLERANCE, MAY NOT BE
SIMPLY A REDUCTION IN NUMBER OF
BETA CELLS AVAILABLE BUT THERE'S
A STRESS, ONGOING STRESS ON
THOSE BETA CELLS THAT DON'T
ALLOW THAT GRANULES TO BE
READILY AVAILABLE AT THE BETA
CELL MEMBRANE FOR QUICK RELEASE.
BEYOND THAT, I DON'T THINK THAT
WE UNDERSTAND THOUGH THE
MECHANISMS UNDERLYING THAT
REDUCTION.
>> THANK YOU.
ANOTHER QUESTION FOR YOU, IN THE
PROMISE DATA, DID YOU GUYS TRACK
PHYSICAL ACTIVITY AND WAS THIS
RELATED TO INSULIN GLUCOSE?
>> GREAT QUESTION.
WE DID NOT.
AND IN HINDSIGHT WE WISH WE
WOULD HAVE.
BUT THE PROMISE PARTICIPANTS ARE
ALREADY DOING A LOT, AS YOU CAN
SEE, JUST WHAT PRADEEP HAS
PRESENTED AND OTHER ARMS OF THE
STUDY.
WE NEEDED TO BALANCE HAVING
PERFECT WITH WHAT'S PRACTICAL IN
THIS BIG STUDY.
>> TWO MORE QUESTIONS, ONE
RELATED TO -- DURING THE PROMISE
STUDY ANY RELATIONSHIP BETWEEN
WHAT YOU SAW IN THE DEVELOPMENT
OF OBESITY AND ONSET OF
CF-RELATED DIABETES?
HAVE YOU LOOKED AT THAT DATA
YET?
>> GREAT QUESTION.
WE HAD TWO OR THREE INDIVIDUALS
WHO PROGRESSED TO CFRD.
IF WE LOOK AT -- I HAVE ACCESS
TO A LIMITED DATASET SUGGESTING
ENDOCRINE SUBSTUDY WITH 75
INDIVIDUALS WITH OGTT AND 135
WITH DEXA.
SO TALK ABOUT THE DATA THAT I
HAVE, ABOUT 13% WERE OVERWEIGHT,
AT BASELINE.
ONE OR TWO OBESE.
AND THEN AFTER 12-18 MONTHS,
ABOUT 25% WERE OVERWEIGHT WITH
ONE OR TWO WHO WERE OBESE.
WE COULD NOT FIND A RELATIONSHIP
BETWEEN BMI OR CHANGE IN BMI AND
RELATIONSHIP WITH WORSENING
GLUCOSE TOLERANCE BASED ON THE
DATA WE HAVE THUS FAR.
>> THE LAST QUESTION I'LL ASK
YOU IS ABOUT BONE.
DO YOU HAVE ANY EVIDENCE THAT
EFFECTS OF CF-RELATED DIABETES
ON BONE ALSO IMPACTS IMMUNE CELL
PRODUCTION OR CAUSES DAMAGE TO
BONE MARROW-DERIVED STEM CELLS?
>> I DON'T THINK WE HAVE DATA
WITH RESPECT TO CF-RELATED
DIABETES.
WE KNOW IN NON-CF DIABETES IS
ASSOCIATED WITH INCREASED RISK
OF FRACTURE AND BONE FRAGILITY.
MECHANISMS INCLUDE CALCIUM LOSS,
GLYCATION OF COLLAGEN THAT
CAUSES BONE FRAGILITY, AND NOW
THERE'S EMERGING EVIDENCE FOR
THE ROLE OF THE ENTEROBONE
ACCESS, THERE ARE RECEPTORS ON
OSTEOBLASTS RESPONSIVE NOT ONLY
TO INSULIN BUT ALSO TO THE
HORMONES SECRETE AND AUGMENT
NORMAL INSULIN SECRETION.
I CAN'T TELL YOU THERE'S DATA IN
CF AND MOST OF THE DATA IN CF
WITH RESPECT TO DIABETES WILL BE
OLDER DATA.
WE KNOW INDIVIDUALS WHO PRIOR TO
ETI WHO HAD CF-RELATED DIABETES
ALSO TEND TO BE SICKER, MORE
LIKELY TO HAVE BONE FRAGILITY SO
I THINK IT'S DIFFICULT TO
UNTEASE THOSE AND WE'LL HAVE
BETTER INSIGHT INTO WHAT'S GOING
GOING FORWARD BETWEEN
ENTEROINSULAR ACCESS AND BONE.
A LOT OF "I DON'T KNOW" THERE.
>> THINGS WE STILL NEED TO
FIGURE OUT.
I'LL ASK QUESTIONS TO JESSICA
NOW.
ARE THERE ANY EMERGING
GUIDELINES FOR CHANGES IN BMI
FOR KIDS OR ADULTS TRIGGERING
ADDITIONAL MONITORING?
>> THE CF FOUNDATION IS WORKING
CURRENTLY ON NEW GUIDELINES.
THERE'S A GROUP WORKING ON THAT
ONE.
THE AMERICAN ACADEMY ON
NUTRITION DIETETICS PUT OUT
GUIDELINES ABOUT ONE OR TWO
YEARS AGO, AND THE BOTTOM LINE
FOR THAT GUIDELINE, I HAVE A
FEELING BOTTOM LINE FOR UPCOMING
GUIDELINES WILL BE TO MONITOR
WEIGHT AND BMI, AND A LOT WILL
BE MORE INDIVIDUAL
RECOMMENDATIONS.
SO IF SOMEONE IS GAINING TOO
MUCH WEIGHT, YOU KNOW, WE SORT
OF PULL BACK ON THE CALORIES
OR -- THAT'S FOR ADULTS BUT VERY
CAREFUL PERSONALIZED TREATMENT
IS WHERE THINGS ARE MOVING WITH
CYSTIC FIBROSIS BECAUSE IT'S NO
LONGER GOING TO BE EVERYONE EAT
EVERYTHING THAT YOU CAN.
>> AND RELATED TO THAT WHAT DO
WE UNDERSTAND ABOUT IMPACT OF
EXERCISE INDEPENDENT OF DIE OAT
LEAN BODY MASS OR FAT, IS
DIETARY CHANGE ALONE ADEQUATE TO
RELATE HEALTH GOALS?
>> NOT ENOUGH STUDIES LOOKING AT
EXERCISE AND ACTIVITY IN CF AND
SEDENTARY ACTIVITY BUT STUDIES
IN GENERAL HAVE SHOWN RESISTANCE
EXERCISE, EXERCISE IN GENERAL
IMPROVES HEALTH, STUDIES OUT OF
AUGUSTA HAVE SHOWN THIS.
I'M BIASED, I THINK ABOUT FOOD
ONLY, BUT IT IS BOTH EXERCISE
AND DIET, FOR THE GENERATION
POPULATION ALSO, IMPORTANT FOR
LUNG HEALTH AND OVERALL
LONGEVITY.
>> AND THEN ONE MORE AND WE HAVE
MORE FOR PRADEEP, WHAT ABOUT
NEEDS DURING PERIODS OF INTENSE
GROWTH LIKE PUBERTY?
>> THAT'S ANOTHER AREA WHERE
WE'LL HAVE TO DO A LOT OF
INDIVIDUAL MONITORING.
I DO BELIEVE IN CHILDREN WITH CF
WE STILL WANT TO GROW THE LUNGS,
WE WANT OUR KIDS TO GROW AS MUCH
AS THEY POSSIBLY CAN.
WE'LL BE MONITORING THAT.
INDIVIDUALLY ASSESSING FOR
CALORIE NEEDS.
MY SHORT ANSWER, IT WILL BE
INDIVIDUAL DEPENDING ON THE
GROWTH OF THE CHILD, BUT THAT
BEING SAID, ANOTHER QUESTION
THAT REMAINS IS WHETHER -- DO WE
STRIVE TO HIT BMI PERCENTILE
GOAL OF 50%?
WHAT ARE NEW TARGET GOALS?
DO WE NEED TO CHANGE THE
THRESHOLD?
STILL A LOT OF QUESTIONS I THINK
I'LL DEFER TO DR. KELLY, A LOT
OF "I DON'T KNOWS," AND THINGS
ARE COMING IN THIS NEW WORLD.
>> I APPRECIATE -- THERE'S SO
MANY QUESTIONS IN THE CHAT.
WE'RE TRYING TO MIX IT UP
BETWEEN SPEAKERS.
I WANT TO ASK PRADEEP, A
QUESTION YOU'VE BEEN INTERESTED
IN, ARE THERE ANY DATA OR IDEAS
ABOUT THE DIFFERENCES GENETIC,
METABOLIC OR VIRULENCE WITH HEMP
AND PERSIST AFTER TREATMENT?
>> I'LL ADD TO THE CHORUS OF I
DON'T KNOW.
WE'VE DONE A LITTLE BIT OF
PRELIMINARY ANALYSIS, VERY CRUDE
MICROPARAMETERS TO ASK, DO ANY
OF THEM THAT ARE -- WE CAN
QUICKLY GAUGE BY EYE, CORRELATE
WITH PROPENSITY TO CLEAR
INFECTION.
THE ONLY THING SO FAR THAT SHOWS
AN ASSOCIATION, AGAIN THIS IS
EARLY DAYS IN THE STUDY, IS
STARTING DENSITY OF THE
BACTERIA.
THERE APPEARS TO BE A BIT OF
THRESHOLD SOMEWHERE AROUND 10 TO
THE 6th OR SO, CF USE PER MIL
OF PSEUDOMONAS, IN THE SPUTUM.
IF YOU'RE STARTING PRE-ETI
SPUTUM COUNTS BELOW THAT HIGHER
PROBABILITY OF GOING TO
INFLECTION CLEARANCE THAN IF
SIGNIFICANTLY ABOVE THAT.
COULD BE MECHANISTIC.
WE KNOW HIGHER DENSITY CULTURES
ARE HARDER TO KILL.
COULD BE EPIPHENOMENON TRACKING
WITH SOMETHING ELSE, COULD BE
EPIPHENOMENON RELATED TO
DURATION OF INFECTION, EXTENT OF
GENETIC DIVERSIFICATION OF
ORGANISMS, BUT DON'T KNOW A LOT
BUT THAT'S THE ONLY THING WE'VE
SEEN SO FAR AS SHAKING OUT AS
PREDICTIVE.
>> THANK YOU.
WE'RE EAGER TO LEARN MORE ABOUT
THAT.
JESSICA, THERE'S ANOTHER
QUESTION FOR YOU.
WE'LL BE TALKING MORE ABOUT
PREGNANCY TOMORROW, BUT IS THERE
EVIDENCE THAT SUGGESTS LEGACY
DIET CONTRIBUTES TO INCREASED
RISK OF CONGENITAL
ABNORMALLALITIES COMPARED TO
WITHOUT CFS?
>> I DON'T KNOW THE ANSWER.
I DON'T THINK THERE'S EVIDENCE
IN OUR CF WORLD REGARDING THE
PREGNANCY AND OTHER OUTCOMES.
THERE'S A LOT OF INFORMATION ON
DIET AND OBESITY STATUS OF THE
MOTHER AND EPIGENETIC CHANGES
THAT OCCUR IN THEIR INFANTS.
I THINK THERE'S A LOT WE CAN
LEARN AND SHOULD LEARN FROM THE
GENERAL OBESITY AND GENERAL TYPE
2 DIABETES EFFECTS ON PREGNANCY
THERE.
>> GREAT.
AND THEN LASTLY, I THINK -- OH,
SO MANY QUESTIONS HERE.
HAVE WE SEEN INCREASED NEED FOR
GLUTEN-FREE DIETS OR ANY OTHER
CHANGES IN PEOPLE'S DIETS WHEN
PEOPLE START HEMPT?
ARE WE UNEARTHING TOLERANCES OF
THINGS THEIR BODIES WEREN'T
SEEING BEFORE?
>> IT'S A REALLY GOOD QUESTION.
HISTORICALLY, THERE IS A HIGHER
PREVALENCE OF CELIAC DISEASE,
NOTHING HAS BEEN PUBLISHED,
SOMETHING WE CAN LOOK TOWARDS IN
LOOKING AT CHANGES IN DIET AND
TOLERANCES.
>> EXCELLENT.
MARA, HAVE WE MANAGED TO HIT THE
QUESTIONS?
>> YES.
WE STILL HAVE QUITE A BIT OF
QUESTIONS THAT WE WILL TRY TO
ANSWER IN THE CHAT BECAUSE WE'RE
NEARING THE END OF THIS SESSION.
SO BE ON THE LOOKOUT FOR THOSE.
WE DID GET TO MOST.
SO THANK YOU VERY MUCH.
WELCOME BACK.
WE'RE GOING TO HAVE ANOTHER
SESSION OF COMMUNITY MEMBER
PERSPECTIVES HOSTED BY DR.
CLANCY.
I'LL TURN IT OVER TO THE GUEST
SPEAKERS NOW.
>>HANK YOU, MARA, AND EVERYONE
FOR AN OUTSTANDING WORKSHOP.
AN EXCELLENT SCIENCE AND GREAT
QUESTIONS BEING ASKED.
NEXT SESSION IS ONLY 15 MINUTES
BEFORE WE GO BACK INTO
BREAKOUTS.
AN OPPORTUNITY TO HEAR FROM
PEOPLE NOT SPECIFICALLY
BENEFITED FROM CF CARE
MODULATORS.
WE WANTED TO ENSURE THAT VOICE
WAS HEARD NOW.
THIS IS AN EXCITING TIME FOR SO
MANY PEOPLE WITH CF, ALSO
PERSPECTIVE WE NEED AS WE LOOK
TO THE FUTURE.
I'M JOINED BY PARENTS OF CF
PATIENTS WHO ARE CURRENTLY ARE
NOT ELIGIBLE FOR MODULATORS AND
WILL LEAVE IT TO THEM AND WOULD
LIKE TO INVITE OR INTRODUCE LISA
HAMBURGER, JOINING US I BELIEVE
FROM MARYLAND.
IS THAT CORRECT?
>> THAT'S CORRECT.
>> AND KATE, I FORGOT WHERE
YOU'RE FROM.
WHERE IS HOME FOR YOU?
>> IOWA FOR ME.
>> I'M FROM IOWA, ALL RIGHT.
I'LL TURN IT OVER TO YOU.
THANK YOU FOR JOINING US, YOUR
PERSPECTIVES WILL BE VALUABLE.
OVER TO YOU.
>> HI, EVERYONE.
I WANT TO THANK EVERYONE FOR
LETTING ME SPEAK WITH YOU TODAY.
MY SON MATTHEW IS 30 YEARS OLD,
RECENTLY GOT MARRIED.
A DAY I NEVER THOUGHT I WOULD
SEE OR COULD EVEN IMAGINE.
I HOPE TO SEE MANY MORE
MILESTONES LIKE THIS ONE.
HE HAS TWO NONSENSE MUTATIONS, G
542X AND W 1282X, NO CURRENT
MODULATOR AT 8 WEEKS OLD, GENE
THERAPY WAS CONSIDERED A
POTENTIAL CURE.
I WAS TOLD AT THE TIME THAT
WITHIN 7 TO 10 YEARS THERE WOULD
BE A CURE.
OBVIOUSLY THAT DID NOT HAPPEN.
AS GENE THERAPY DID NOT WORK OUT
AS PLANNED DURING THAT TIME
PERIOD.
I REMAINED HOPEFUL AS I DO
TODAY.
THERE HAVE BEEN OTHER ADVANCES
IN RESEARCH WITH MEDICATIONS,
BUT DO NOT TREAT UNDERLYING
CAUSE OF CF.
MY SON HAS HAD CHALLENGES,
MOSTLY WITH G.I. ISSUES
INCLUDING RUPTURED BOWEL AT 14
WHERE WE ALMOST LOST HIM, SEVERE
SINUS ISSUES.
HE'S COMPLIANCE WHICH HELPS
MAINTAIN A HIGH PULMONARY
FUNCTION AND FEW EXACERBATIONS
FEELS THE OLDER HE GETS THERE
WILL BE MORE CHALLENGES HARDER
TO MAINTAIN HELP WITHOUT A
MODULATOR.
SO WHAT DOES THIS MEAN FOR THOSE
LIKE MY SON WHO ARE NOT
ELIGIBLE?
MEDIAN LIFE EXPECTANCY IS AROUND
50 YEARS OLD, OBVIOUSLY NOT GOOD
ENOUGH.
ALTHOUGH I LOOK AT THIS AND HOW
THIS RELATES TO INDIVIDUALS
WITHOUT CURRENT MODULATORS, THIS
MAY NOT BE A TRUE INDICATOR
WITHOUT A MODULATOR.
THEY HAVE INCREASED ABILITY FOR
WOMEN TO HAVE CHILDREN,
MODULATORS HAVE BEEN DIRECT
CAUSE FOR TRIPLING IN THE LAST
YEAR, FOR THOSE WITHOUT WHERE DO
THEY STAND?
WE KNOW THE OBVIOUS RESULTS ARE
FEWER HOSPITALIZATIONS, LESS
LUNG AS EXACERBATION AND.
THEY HAVE BEEN SHOWN TO ENHANCE
ONE'S QUALITY OF LIFE BUT
WITHOUT THE MODULATOR THIS IS
NOT THE CASE.
THE BIGGEST DIFFERENCE WOULD BE
CHILDREN BEING BORN TODAY.
IF THEY HAVE A CHANCE AT AN
EARLY AGE TO START A MODULATOR
THERE'S LESS OF A CHANCE FOR
LUNG DAMAGE AND MANY OTHER
COMPLICATIONS ASSOCIATED WITH
CF.
THIS IS WHY WORK NEEDS TO
ACCELERATE SO ALL BABIES BEING
BORN WITH CF TODAY HAVE THE SAME
RESULTS.
I SPEAK WITH MANY ADULTS WHO
DISCUSSED TRANSFORMATION NOT
ONLY OF THEIR HEALTH BUT MENTAL
HEALTH IN THAT THEY NOW LOOK
FORWARD TO REACHING MILESTONES
THAT THEY NEVER THOUGHT
POSSIBLE.
VERSUS THOSE WHO DON'T HAVE A
MODULATOR THAT WORRY ABOUT THEIR
FUTURE AND WHAT IT HOLDS FOR
THEM.
THEY DO NOT REBOUND AS QUICKLY
AS BEFORE AS EACH EXASPERATION
BUILDS.
CF TAKES A TOLL ON PHYSICAL AND
MENTAL HEALTH AND THOSE WHO
CURRENTLY DO NOT HAVE A
MODULATOR FEEL LIKE THEY CAN NOT
NECESSARILY PLAN FOR THE FUTURE.
FOR SOME, THERE'S A WEIGHT OF
BEING LEFT BEHIND, THAT NEEDS TO
BE CHANGED SO ALL PEOPLE WITH CF
HAVE THE SAME OPPORTUNITIES
MOVING FORWARD.
WITH mRNA TECHNOLOGY IN THE
NEWS TODAY DUE TO AC SELL
ACCELERATION OF COVID VACCINE
WE'RE LOOKING FORWARD TO SIMILAR
TECHNOLOGY.
THERE'S BEEN DISCUSSIONS THAT
MAY CONNECT THE CURE WITH
FINDING SOMETHING FOR THOSE WITH
NONSENSE MUTATION, UTMOST
IMPORTANCE RESEARCH ACCELERATES
AT A BRISK PACE.
OVER THE 30 YEARS I'VE BEEN
INVOLVED WITH THE CF FOUNDATION,
AS A PARENT, VOLUNTEER, BOARD
MEMBER, I'VE WITNESSED GROWTH IN
RESEARCH DEVELOPMENT AND
COMMITMENT TO FINDING A CURE FOR
ALL REGARDLESS OF ONE'S
MUTATION.
NO ONE WILL REST UNTIL THERE'S A
CURE FOR ALL PEOPLE WITH CF.
WE MUST STAY ON COURSE.
WE KNOW AS RESEARCHERS YOU WON'T
STOP UNTIL THERE'S A CURE FOR
EVERYONE WITH CF BUT IN THE
MEANTIME THOSE WITHOUT A
MODULATOR NEED TO KEEP FIGHTING
UNTIL THEY GET THEIR MODULATOR
AND A CURE.
THANK YOU.
>> THANK YOU, LISA.
I'M KADE HAMMES, HERE IN IOWA,
OUR CARE CENTER IS UNIVERSITY OF
IOWA
OUR DAUGHTER MILA IS 3 YEARS
OLD, WE GOVERNMENT THE DREAD --
GOT THE DREADED PHONE CALL AT 10
DAYS OLD, THE FIRST STEP IN
LEARNING, OUR CALL WAS -- MY
WIFE IS A NURSE PRACTITIONER,
SHE WAS BAWLING AND CRYING, I
HAD NO IDEA WHAT CF WAS.
I'M CURIOUS WHY MY WIFE IS
BAWLING.
THE LADY ON THE PHONE TELLS US
DON'T RESEARCH WITH GOOGLE,
DON'T LOOK UP WHAT CF IS.
YOU'LL REGRET IT.
HERE IS MY WIFE, SHE'S BAWLING,
WHAT DO I DO?
WE GOOGLE IT.
AND SO YOU QUICKLY LEARN KIND OF
THE OLD STATISTICS, ALL THE OLD
OUT OF DATE THINGS THAT CF,
NOBODY'S LIVING BEYOND
CHILDHOOD, ALL OF THESE OLD
STATS THAT PROBABLY DON'T MEAN
MUCH ANYMORE.
SO IT INSTANTLY PUT THE FEAR IN
MYSELF AND MY WIFE, SHE WAS
FAMILIAR, BUT DIDN'T TOTALLY
UNDERSTAND IT.
MY DAUGHTER WAS BORN THE YEAR
TRI CAFTA CAME OUT.
SHE WAS BORN IN APRIL, IT CAME
OUT IN OCTOBER. THERE WAS
EXCITEMENT IN THE RESEARCH TEAM
WITH EVERYBODY WE WERE TALKING
TO ABOUT CF.
IT'S A TOTALLY DIFFERENT DISEASE
TODAY, YOU CAN'T LOOK AT GOOGLE,
IT'S ONE OF THOSE THINGS BECAUSE
OF THE MODULATORS THESE KIDS
COULD LIVE VERY LONG LIVES, WE
HAVE NO IDEA WHAT THE CEILING
IS, AGE IS JUST A NUMBER.
BUT THE PROBLEM WAS I KEPT
DIGGING IN AND TRYING TO
UNDERSTAND AND RESEARCH FOR MY
OWN BENEFIT, EVERYTHING I'M
UNDERSTANDING IS IT'S ABOUT
CERTAIN MUTATIONS AND OUR
DAUGHTER SEEMS TO HAVE A
MUTATION THAT THESE DON'T WORK.
OUR CARE TEAM WASN'T 100% SURE
AT THE TIME BUT HELPED US DIG IN
AND START TO RESEARCH AND THAT
WAS KIND OF THE TRUTH WE ENDED
UP FINDING WAS SHE JUST HAS TWO
CLASS 1 MUTATIONS, ONE IS A
FRAME SHIFT, ONE IS A SPLICE.
BUT NEITHER OF THEM ARE ON THE
LIST OF THINGS THAT TRICATFA
WILL BENEFIT EVEN WITH THERA
TYPING, THEY ARE WORKING ON THE
NONSENSE WITH THE READ-THROUGH,
NEITHER OF HERS WOULD BE
BENEFITING FROM THOSE MODULATORS
SO IT'S BECOME THAT GUT FEELING
OF, OKAY, WHAT ABOUT US?
WHERE IS THE MODULATOR THAT'S
GOING TO CHANGE OUR LIFE?
ALL AROUND US IT'S GREAT TO BE
EXCITED FOR EVERYBODY ELSE AND
SEEING HOW HAPPY EVERYBODY IS
AND SEEING THE ADVANCEMENTS THAT
ARE HAPPENING, AND SO MANY IN
THIS CF COMMUNITY ARE JUST --
IT'S A WONDERFUL FAMILY, A
FAMILY WE DIDN'T WANT BUT THEY
ARE AMAZING PEOPLE WITHIN OUR
FAMILY OF CF AND THEY ARE
TELLING US, HEY, WE'RE NOT
STOPPING TILL THE FIGHT IS DONE.
WE'RE GOING TO BE WITH YOU EVERY
STEP OF THE WAY.
THEY GIVE US THE ENCOURAGEMENT
THAT BACK WHEN WE FOUND OUT WE
HAD CF THERE WAS NO HOPE, AT
LEAST THAT'S THE WAY IT FELT.
WE'VE SEEN THE ADVANCEMENTS IN
PROGRESSION.
SO FROM OUR STANDPOINT MY WIFE
AND MYSELF, IT'S LEARNING TO
TRUST EVERYBODY ELSE'S
EXPERIENCE THAT WE'RE GOING TO
GET THERE AND WE'RE GOING TO SEE
THIS.
SO IT'S CONSTANTLY TRYING TO
EDUCATE OURSELVES.
I'VE ACTUALLY ATTENDED MANY
RESEARCH OPPORTUNITIES WITH AT
LEAST VIDEOS AND LEARNING FROM
JP BEFORE, I'VE SEEN HIM QUITE A
FEW TIMES NOW, TRYING TO
UNDERSTAND I HAVE A LIST OF LIKE
EVERY COMPANY THAT HAS A DRUG
THAT THEY ARE WORKING ON WHETHER
CLINICAL OR PRE-CLINICAL, THAT
COULD POTENTIALLY HELP MY
DAUGHTER.
LIKE THE mRNAs, THE GENE
THERAPY SPLICE SENSE IN ISRAEL,
ANYTHING THAT COULD POTENTIALLY
HELP HER IN THE FUTURE IS
SOMETHING I KEEP TRACK OF.
WHAT'S PROBABLY INTERESTS ME THE
MOST, EVERY YEAR ATTENDING
RESEARCH CON, AND LIKE I SAID,
IT'S ONE OF THOSE THINGS WHERE
WE'RE VERY ENCOURAGED BY THE
QUICK ADVANCEMENTS IN THE
RESEARCH AND EVERYTHING, AND NOT
BEING LEFT BEHIND, BUT IN THE
SAME SENSE THERE IS THAT NATURAL
GUT FEELING OF BEING LEFT
BEHIND.
RESEARCH CON WITH THE CYSTIC
FIBROSIS FOUNDATION TWO YEARS
AGO WAS ABOUT THE PATH TO THE
CURE, AND HERE ARE ALL THE DRUGS
WE'RE WORKING ON.
TO BASICALLY GET EVERYBODY
THERE.
THIS YEAR IT FELT LIKE THE
RESEARCH CON WAS ABOUT WHAT IS
LIFE LIKE ON MODULATORS BECAUSE
THERE'S A LOT OF RESEARCH FOR
THOSE THAT HAVE MODULATORS AND
WHAT IS LIFE LIKE FOR THEM.
AND WE'VE TALKED TO A FEW OF
THEM.
WE JUST HAD OUR WALK.
THERE WAS ANOTHER FAMILY WE WERE
TALKING ABOUT HOW WE MAYBE PUT
OUR CHILD IN MORE OF A BUBBLE
THAN THE NEXT FAMILY, BUT OUR
STANDPOINT ONCE SHE LOSES LUNG
FUNCTION WE CAN'T GET IT BACK.
IF A MODULATOR'S IN HER FUTURE
CAN WE KEEP HER LUNG FUNCTION AS
GOOD AS POSSIBLE UNTIL WE CAN
GET ON THAT MODULATOR, SO WE TRY
VERY HARD.
WE CULTURE STAPH FREQUENTLY BUT
LUCKILY HAVE NOT HAD TO DEAL
WITH PSEUDOMONAS, A LOT OF
FAMILIES IN OUR AREA HAVE BEEN
DEALING WITH PSEUDOMONAS,
CULTURING IT NOW, CAN'T GET RID
OF IT.
ONE PARENT TOLD ME MY SON HAS
BEEN ON MODULATOR VERY EARLY ON,
HE'S LIKE I THINK MAYBE WE
RELAXED TOO MUCH BECAUSE OF
BEING ON IT.
SO THERE'S A LOT OF RESEARCH
HAPPENING THAT NEEDS TO HAPPEN
FOR THOSE THAT QUALIFY, BUT THAT
RESEARCH CON THIS YEAR LIKE I'M
SO USED TO TALKING ABOUT
MODULATORS IN DEVELOPMENT AND
THINGS THAT COULD GO FOR HER TO
IT WAS LIKE IT FELT LIKE A SHIFT
TO EVERYBODY'S JUST CONCERNED
ABOUT WHAT IS LIFE LIKE AFTER
THE MODULATORS.
THAT WAS KIND OF THE, OH, CRAP,
ARE WE BEING LEFT BEHIND MOMENT,
A SINKING FEELING.
I KNOW I'VE READ IT ENOUGH
PLACES NOW THAT WE WON'T BE LEFT
FIND, THE CF FOUNDATION AS
REPEATEDLY SAID IT, EVERY PARENT
EVEN THOUGH THEIR CHILD HAS A
MODULATOR NOBODY IS GOING TO
STOP.
SO THAT'S ALL VERY ENCOURAGING,
AND I JUST -- WE WANT TO TALK TO
THE RESEARCHERS AND ANYBODY WE
CAN ENCOURAGE TO KEEP THAT FOCUS
ON THAT LAST, IT'S STILL LIKE
10% THAT ARE LOOKING FOR THAT
THING TO HELP THEM UNTIL A CURE
CAN BE FOUND LATER ON.
LET'S NOT GIVE UP ON THEM.
THERE'S THINGS OUT THERE THAT
CAN WORK AND WE KNOW THERE ARE
SO LET'S KEEP THE FOCUS UNTIL
THERE'S AT LEAST SOMETHING FOR
EVERYBODY.
THAT'S MY BIG PLEA.
I GUESS WHY I'M HERE ATTENDING,
BUT I'M HAPPY TO TAKE QUESTIONS
ANYTIME, JP.
>> THANK YOU BOTH SO MUCH FOR
GIVING US THAT REALLY VALUABLE
PERSPECTIVE AND I HOPE THE
MESSAGE, YOU'VE BEEN ABLE TO
LISTEN TO SESSIONS TODAY, THE
RESEARCH COMMUNITY AND THE CARE
COMMUNITY IS COMMITTED TO ALL
PEOPLE WITH CF AND EXTENDS WELL
BEYOND THE BORDERS OF CF
FOUNDATION BUT THE ENTIRE
COMMUNITY.
I GUESS WE HAVE TWO MINUTES
BEFORE WE BREAK INTO BREAKOUTS.
I WOULD ASK IS THERE ANY -- I
THINK KADE, YOU MENTIONED THAT.
LISA, ANYTHING YOU'D LIKE TO
SHARE OR TELL RESEARCHERS FROM
YOUR HEART ABOUT WHAT WOULD BE
MEANINGFUL TO YOU?
THAT'S MAYBE ONE PIECE I WOULD
LOVE TO HEAR.
>> WELL, THE FACT THAT, YOU
KNOW, MY SON IS 30, AND, YOU
KNOW, IF THE TIME ISN'T RUNNING
OUT, BUT IT FEELS LIKE TIME IS
RUNNING OUT, THE OLDER HE GETS.
AND I WOULD SAY, YOU KNOW, I
HAVE THE STRONG BELIEF, HAVE
BEEN INVOLVED LONG ENOUGH WITH
THE FOUNDATION TO KNOW WE WILL
NOT BE LEFT BEHIND, AND IT'S A
SPEECH, YOU KNOW, WHEN I ATTEND
ANYTHING LIKE VLC OR ANYTHING
ELSE THAT, YOU KNOW, WE KEEP
GIVING, THAT WE'RE STILL HERE,
WE'RE THE 10%.
SO, I FEEL STRONGLY THAT PEOPLE
ARE COMMITTED.
IT'S JUST THE TIME FRAME OF
GETTING TO THAT POINT, YOU KNOW,
THAT I GUESS WORRIES ME THE
MOST, YOU KNOW, HOW MUCH LONGER
CAN MY SON HANG ON TO HIS 93%
LUNG FUNCTION AND, YOU KNOW,
WHILE IT'S HIGH FOR SOMEONE HIS
AGE IT'S GETTING HARDER AND
HARDER.
AND, YOU KNOW, WE JUST ALL WANT
OUR SOMETHING, WHETHER IT'S A
MODULATOR, CURE, WHATEVER IT IS.
AND, YOU KNOW, WE'RE A LITTLE
BIT HOPEFUL ABOUT THE ELOCK
STUDY AND OTHER STUDIES GOING ON
FOR SOMETHING SPECIFIC FOR HIS
MUTATION BUT, YOU KNOW, WE'RE
TRYING TO HANG IN THERE, BUT
HOPEFULLY EVERYONE HERE IS ON
BOARD AND WILL TRY TO HELP US
ACCELERATE, YOU KNOW, CLOSER TO
THE MODULATORS OF THE CURES WE
NEED.
>> THOSE ARE GREAT WORDS OF
WISDOM.
AND ALSO MARCHING ORDERS FOR US
TO KEEP GOING.
THANK YOU BOTH.
LISA, KADE, REALLY APPRECIATE
YOU SHARING PERSPECTIVES.
WE'LL HAVE BREAKOUTS COMING NOW.
MARA WILL COME BACK AND GIVE US
A BIT MORE DIRECTION.
I THINK YOU HAVE SORT OF THE
LINKS.
THANK YOU.
WELCOME BACK TO THE MAIN
WORKSHOP ROOM.
THANK YOU ALL FOR PARTICIPATING
IN OUR BREAKOUTS THIS AFTERNOON.
I WANT TO GIVE YOU LOGISTICS
ABOUT WHAT WE'RE DOING OVER THE
NEXT HOUR BEFORE WE CLOSE OUT
THE WORKSHOP.
>> RECORDING IN PROGRESS.
>> WE'RE HERE TO REGROUP AND
RECAP FROM THE BREAKOUT ROOMS.
WE'LL DISPLAY THE BOARDS FROM
EACH BREAKOUT ROOM AND WE WILL
HAVE THE SESSION MODERATORS
DISCUSS THE DISCUSSION THAT
HAPPENED WITHIN THAT ROOM.
AND SOME OF THE TOPICS THAT ROSE
TO HIGH PRIORITY FOR EACH OF
THOSE ROOMS.
SO WE'RE ASKING THAT EACH OF THE
BREAKOUT ROOMS REPORT OUT FOR
ABOUT TEN MINUTES EACH.
AND THEN AT THE END WE WILL BE
SHOWING A FOURTH BOARD, AND THAT
WILL HAVE THREE TO FIVE OF THE
TOP-VOTED TOPICS THAT CAME OUT
FROM EACH OF THE BREAKOUT ROOMS.
SO, THAT WILL GIVE US AN
OPPORTUNITY TO SPEND THE LAST 30
MINUTES OF THE MEETING IN A
GENERAL DISCUSSION THAT WILL BE
LED BY WORKSHOP CO-CHAIRS ABOUT
SOME TOPIC THAT ROSE TO THE TOP
FROM EACH OF THE ROOMS.
NOW, I WANT TO LET YOU KNOW THAT
WE'RE KEEPING ALL IDEAS, SO
THANK YOU FOR YOUR
PARTICIPATION.
I THOUGHT THERE WAS A LOT OF
GREAT IDEAS ON THESE BOARDS,
FROM EACH OF THE ROOMS, BUT WE
DO WANT TO HAVE A MORE
NARROW-FOCUSED DISCUSSION ON
SOME THINGS THAT GOT MORE VOTES
FROM EACH OF THE ROOMS.
WE'LL DO THAT IN THE LAST HALF.
SO THAT'S GOING TO BE THE
STRUCTURE FOR THE DISCUSSION FOR
THE NEXT HOUR.
AND WITH THAT, LET'S PULL UP THE
BOARD FROM BREAKOUT 1.
I WILL TURN IT OVER TO THE
MODERATORS FOR THAT ROOM.
>> IS AP HERE?
>> WE HAD A GREAT DISCUSSION.
I WAS CO-MODERATING WITH AMY
RYAN, AND AP NAREN, SUMMARIZING
THE MAIN FINDINGS AND WE'LL
CHIME IN.
>> THANK YOU VERY MUCH.
THIS WAS A WONDERFUL SESSION.
WE ENJOYED IT.
IT WAS PATIENT-DERIVED MODEL
SYSTEMS.
WE WENT OFF FOUR TOPICS, CURRENT
USES OF PATIENT DERIVED MODELS
AND SYSTEMS, AND MODEL SYSTEMS
AND ADVANTAGES AND LIMITATIONS,
RELEVANCE OF PERSONALIZED MODEL
TO THE CLINIC.
AND OTHER TOPICS.
THE DISCUSSION WAS VERY LIVELY.
WE HAD A LOT OF INPUT FROM
EVERYBODY.
SO, ONE OF THE HIGHEST VOTE
GETTERS WAS DO WE NEED A COMPLEX
MODEL INCORPORATING
BIOENGINEERING, TO WE NEED MORE
COMPLEX MODELS INCORPORATING
BIOENGINEERING INFLAMMATION THAT
BETTER REFLECTS IN VIVO
SITUATION, CAN THAT BE ADAPTED
TO HIGH-THROUGHPUT?
WHAT DID WE MEAN BY THAT?
CAN WE SEE WHAT WE SEE IN THE
AIRWAY IN MOUSE MODELS, RELATED
BACK TO DIFFERENT ANIMAL MODEL?
CAN WE HAVE A MORE COMPLEX MODEL
LIKE LUNG OR PANCREAS IN A CHIP,
IS THE THROUGHPUT FOR THESE
LIMITING USE, NEED COLLABORATION
BETWEEN INFLAMMATION AND
EPITHELIAL EXPERTS,
BIOENGINEERING COLLABORATIONS.
THIS IS A COMPLEX SET OF STUDIES
BUT I THINK A LOT OF INTEREST
WAS SHOWN IN THIS PARTICULAR
VISIT.
THE SECOND MOST HIGHLY VOTED WAS
THIS PARTICULAR TOPIC IN WHICH
ARE PERSONALIZED MODEL SYSTEMS
CRITICAL IN DEVELOPING
THERAPEUTIC OPTIONS FOR RARE
MUTATION, INFLAMMATION AND
INFECTION, AND SEE IF YOU'RE
UNDERSTANDING INFECTION.
ONE OF THE IDEAS, NOT ONLY TO
LOOK AT SPECIFIC PATIENT-DERIVED
MODEL SYSTEM, INCORPORATE iPSC
TECHNOLOGY AS WELL.
IN SOME CASES IT WOULD BE
IMPOSSIBLE TO GET PRIMARY CELLS
AND THE IDEA IS WHETHER THERE
ARE SOME LIMITATIONS TO THAT,
WHETHER IT WOULD MIMIC PRIMARY
CELLS WAS THE QUESTION.
RELEVANCE OF NASAL CELLS TO
PREDICT BRONCHIAL RESPONSES,
SOME QUESTIONS WERE ASKED.
AND THE THIRD MOST HIGHLY VOTED
TOPIC, SHOULD STANDARDIZED
METHOD BE DEVELOPED TO ALLOW
COMPARISON ACROSS LABORATORIES.
THERE WAS A LOT OF INTEREST IN
THIS BECAUSE THE IDEA IF WE WERE
GOING INTO TESTING IN PATIENT
DERIVED SYSTEMS, THAT WE NEEDED
TO HAVE STANDARDIZED ASSAYS
REPRODUCED BETWEEN LABS, AMONG
LABS, WITHIN LABS, SO THERE WAS
A LOT OF INTEREST IN THAT.
THERE WERE SEVERAL OTHER TOPICS
THAT GOT A LOT OF VOTES BUT I'M
NOT GOING TO HIGHLIGHT THAT.
THESE WERE THE THREE TOP
VOTE-GETTING TOPICS, I WILL
PAUSE AND SEE IF MARTINA OR AMY
WANTS TO CHIME IN.
>> AP SUMMARIZED WELL , GETTING
MORE COMPLEX MODELS, TRANSLATION
TO CLINIC, MISSING INFLAMMATION
WHICH WAS A LARGE PART OF THE
DISCUSSION.
>> AND FUNCTION WHICH BETTER
MODELS MIGHT MAKE FEASIBLE, AND
COMPLEXITY OF MODELS COULD
BETTER REFLECT TISSUE STRUCTURE,
THERE WAS THE IDEA OF
INCORPORATING NEUTROPHILS TO GET
MORE TO THE REALITY OF
INFLAMMATORY RESPONSES, AND
MAYBE NOT REFLECTED IN THE TOP
VOTES BUT RELATED TO IMPROVING
MODELS, TO GET A MORE
HIGH-THROUGHPUT PLATFORM FOR
TESTING.
WHAT WAS ALREADY MENTIONED, WAS
REPEATEDLY DISCUSSED, MODELS
SHOULD REALLY REFLECT IN VIVO
ENVIRONMENT OF CF EPITHELIA
WHICH IS OBVIOUSLY INFECTION
INFLAMMATION, SO COULD BE
ADVANCED BY CULTURE, BACTERIA,
LOOKING AT INFLAMED MODELS TO
STUDY ANTI-INFLAMMATORY AND ALSO
THERAPEUTICS.
THERE WAS DISCUSSION ABOUT
PARTICLE DELIVERY IN
RELATIONSHIP TO MACHINE THERAPY,
AND THIS COULD ALSO BE MUCH MORE
RELEVANT STUDIED IN MODELS THAT
REFLECT THE TISSUE BY HAVING
PHARMACOKINETICS MORE RELATED TO
THE EPITHELIA IN VIVO AND ALSO
RELEVANT SYSTEM.
>> ANOTHER TOPIC THAT WAS
DISCUSSED, PERSONALIZED MODELS
ASPECT, WAS HOW GOOD ARE NASAL
EPITHELIAL CELLS WHICH ARE MORE
SUCCESSFUL AT PREDICTING IN
OTHER AREAS OF THE AIRWAY AND
OTHER TISSUES, CAN THEY BE USED
AS FIRST STEP IN SCREENING IN A
PERSONALIZED MANNER.
THAT THAT CAME UP UNDER A FEW OF
THE COMMENTS THAT ARE THERE BUT
DOESN'T APPLY TO THE
PERSONALIZED MODELS.
>> IN REGARD TO IMPROVING MODELS
THERE WAS ALSO THE IDEA USING
DIFFERENT SECTIONS OF THE G.I.
TRACT BECAUSE THEY ARE DIFFERENT
WHICH GETS BACK TO MAYBE NASAL
AND BRONCHIAL ARE NOT REALLY
IDENTICAL, WITH NUCLEOTIDES.
>> ALSO UPPER AND LOWER AIRWAYS.
>> SMALL AND LARGE AIRWAYS,
YEAH.
WHAT DIDN'T GET THE MOST VOTES,
AP MIGHT HAVE MENTIONED QUICKLY,
COMPARISON OF ANIMAL MODELS TO
IN VITRO MODELS.
PARTICULARLY HUMAN PRIMARY
CULTURES TO FINDINGS IN ANIMAL
MODELS.
I THINK ALEXANDRA WANTED TO ASK
SOMETHING.
>> JUST A COMMENT, MARTINA, BUT
VERY ENDS OF OUR SESSION, ANIMAL
MODELS SESSION, SOMEONE POPPED A
COMMENT ABOUT DO WE NEED SOME IN
VITRO MODEL TO REPLICATE
SPECIFIC ASPECT OF THE -- WHAT
WE FIND IN ANIMAL MODELS, SO IT
LOOKS LIKE THE CONVERSATION IS
CONVERGING ON A CONTINUUM THAT
GOES FROM IN VIVO TO IN VITRO,
AND EVERYTHING IN BETWEEN.
I THINK ONE OF THE BIG THINGS
THAT CAME OUT OF OUR DISCUSSION
WAS IF WHAT YOU FIND IS
REPLICATED IN DIFFERENT MODELS,
YOU CAN TRUST IT A LITTLE BIT
MORE.
SO, I'M HAPPY TO HEAR THAT.
>> THAT'S A GOOD POINT.
>> THIS IS ALSO A GREAT SEGUE TO
MOVING INTO THE REPORT OUT FROM
THE SECOND SESSION.
>> SUPER.
>> THEY WILL CALL UP THE BOARD
FROM BREAKOUT 2.
>> I HAVE IT OPEN.
I CAN SHARE IT RIGHT NOW.
>> IF YOU HAVE SCREEN SHARING
CAPABILITIES, THAT'S FINE.
>> HERE WE GO.
SO, ANIMAL MODEL SESSION HAD A
GOOD DISCUSSION.
WE STARTED WITH THREE MAJOR
AREAS THAT WE DISCUSSED, I'M
GOING TO GO OVER THE TOP FIVE.
WHAT PRESSING CLINICALLY
RELEVANT QUESTIONS REGARDING
HIGHLY EFFECTIVE MODULATOR
THERAPIES REQUIRE
EXPERIMENTATION IN ANIMALS.
ONE OF THE HIGHEST SOURCE,
SECOND FROM THE TOP, WAS USING
THE ANIMAL MODELS TO GET A
PATHOLOGY OF NON-EPITHELIAL CELL
COMPARTMENTS, AND I INTERPRET
THIS THAT OFTEN PROBABLY THE NIH
STUDY SECTIONS, YOU KNOW, FAVOR
ORGAN -- YOU KNOW, THE STUDY OF
ORGANS THAT GET EPITHELIAL
DISEASE WHERE CFTR IS MOST
CHARACTERIZED, BUT I THINK IT'S
RELEVANT TO THE FACT THAT THERE
ARE GOING TO BE MANY NEW
PHENOTYPES EMERGING FROM HIGHLY
EFFECTIVE MODULATOR THERAPY IN
CF PATIENTS THAT WE DON'T
UNDERSTAND, AND IT'S POSSIBLE
THAT THIS TYPE OF -- THESE TYPES
OF EPITHELIAL POPULATIONS,
SMOOTH MUSCLE, BONE, VASCULAR,
COULD BE VERY IMPORTANT TO THOSE
NEW PHENOTYPES.
THERE'S ALSO COMMENTED OVER HERE
TOO UNDER -- ABOUT
CARDIOVASCULAR DISEASE,
INCREASED INCIDENCE IN CF
PATIENTS.
SECOND REALLY HAS TO DO WITH
CHRONIC DISEASE STATE,
DISCUSSION ABOUT REVERSIBILITY
EVER BRONCHIECTASIS.
HOW ANIMAL MODELS COULD BE USED
TO ADDRESS THAT.
THERE WAS ANOTHER SESSION THAT
WAS TALKING ABOUT CHRONIC
DISEASE STATES, THIS MIGHT BE A
TOPIC WE CAN TALK ABOUT HERE IN
THE COMMON DISCUSSION.
HIGHLY EFFECTIVE MODULATOR
THERAPIES IN PREGNANCY AND
POST-NATAL CARE, DISCUSSIONS
ABOUT THE TIMING OF, YOU KNOW,
WHEN IN UTERO EITHER CONGENITAL
ABNORMALITIES SUCH AS ABSENCE OF
VAS DEFERENS OR EPIDIDYMIS
PRE-MODULATOR THAT CONGENITAL
ABNORMALITIES ARE MORE ABUNDANT
IN THAT POPULATION THAN NORMAL
NON-CF INDIVIDUALS.
SECOND MAJOR AREA THAT I'LL TALK
ABOUT IS WHAT CF MODEL
PHENOTYPES CAN INFORM CLINICALLY
RELEVANT KNOWLEDGE GAPS.
I THINK THIS WOULD BENEFIT
SIGNIFICANTLY FROM HEARING
DURING THE DISCUSSION AT THE END
OF THESE PRESENTATIONS WITH ALL
THE CLINICIANS IN THE AUDIENCE.
THERE WAS DISCUSSION ABOUT CF
PATIENTS ARE NOW -- MALE CF
PATIENTS ARE GETTING MUCH MORE
INTERESTED IN UNDERSTANDING
THEIR FERTILITY PROSPECTS ON
CFTR MODULATORS, AND IT'S THE
CONSENSUS OF THE PIG AND FERRET
GROUPS MODULATORS WOULD HAVE TO
INITIATE IN UTERO IN ORDER TO
PREVENT INFERTILITY IN MALES AT
BIRTH BASED ON THE ANIMAL
MODELS.
SOMEWHAT SIMILAR WITH COULD THE
CHRONIC BRONCHIECTASIS COMMENT,
CHRONIC DISEASE STATES AND
BIOMARKERS THAT COULD PREDICT
NEW CONDITIONS ASSOCIATED IN CF
PATIENTS ON HIGHLY EFFECTIVE
MODULATOR THERAPY.
WE HEARD A LOT IN THE EARLIER
SESSIONS, YOU KNOW, ABOUT SOME
OF THESE.
WE'RE GOING TO HEAR MORE LATER,
BUT I THINK IT'S IMPORTANT BOTH
IN THE CONTEXT OF VERY EARLY
DISEASE PROGRESSION AND THE
PREDICTION OF WHAT CF
PATIENTS -- WHAT THEIR CLINICAL
SITUATION MIGHT BE, MANY YEARS
FROM THE TIME THAT THEY STARTED
HIGHLY EFFECTIVE MODULATOR
THERAPY, THE CF ANIMALS THAT
HAVE SHORTER LIFESPANS COULD
HELP IN THIS.
I MENTIONED THIS PREVIOUSLY AS
WELL, CARDIOVASCULAR DISEASE,
THIS IS A COMMENT BY JEN,
STARTING TO SEE A LOT MORE
MYOCARDIAL INFARCTIONS, AND WILL
CANCER RISE BOTH G.I., CERVICAL,
BUT ALSO PANCREATIC CANCER,
BECAUSE THE MODULATOR THERAPIES
ARE PARTIALLY EFFECTIVE BUT
ORGANS HAVE INCREASED
PROLIFERATION AND TURNOVER.
ALSO COMPARING THE FACT THAT
WE'RE, AS A FIELD LUCKY TO HAVE
SEVEN ANIMAL MODELS, AND
COMPARING THE SIMILARITIES AND
DIFFERENCES BETWEEN THOSE MODELS
CAN BE VERY INFORMATIVE, EVEN IF
THE ANIMAL MODEL DOESN'T GET
DISEASE IN THAT PARTICULAR ORGAN
IT'S PROBABLY INFORMING GENETIC
DIVERSITY IN HUMANS, AND THE
WIDE RANGE OF PHENOTYPES THAT WE
SEE IN CF PATIENTS AND THE LAST
TOP HITTER, AGAIN, RELEVANT
BIOMARKERS HERE, MENTIONED
EARLIER, BUT CAN NEW BIOMARKERS
BE DISCOVERED THAT ARE
PREDICTING THESE EARLY --
PREDICTING THESE NEW DISEASE
STATES, I THINK IDEALLY THOSE
TYPE OF BIOMARKERS WOULD BE
SOMETHING THAT WOULD BE IN THE
BLOOD, AND I THINK IT COULD BE
EXTREMELY USEFUL WITH NEW
SEQUENCING, HIGH-THROUGHPUT
SEQUENCING TECHNOLOGY, IF THINGS
LIKE NON-CODING RNAs OR
microRNAs REACHED OUT OF
CELLS AS THEY TURN OVER COULD
INDEX PARTICULAR PATHWAYS THAT
ARE BEING ACTIVATED THAT PREDICT
THE COURSE OF THE DISEASE STATE.
I UNDERSTAND THIS IS KIND OF
HARD TO FUND THROUGH NIH BECAUSE
IT'S DISCOVERY, BUT I THINK IT'S
RELEVANT TO PUT THE IMPORTANCE
DOWN HERE.
WHY DON'T I TURN IT OVER OR ASK
BRUCE AND SUE, THE OTHER
CO-CHAIRS, ON THIS SESSION, DO
YOU HAVE ANY COMMENTS, BRUCE,
SUE?
>> YOU DID A GREAT JOB, JOHN,
COVERING THE HIGH POINTS OF OUR
DISCUSSION.
THANKS.
>> GREAT.
>> YEAH, I AGREE.
>> OKAY.
>> MAYBE BEFORE YOU HAVE LIKE
THREE MINUTES IN YOUR
REPORT-OUT, MAYBE BEFORE WE DO
THAT YOU COULD ADDRESS FELIX'S
QUESTION IN THE CHAT.
DO WE NEWS A ROBUST CF
BRONCHIECTASIS ANIMAL MODEL?
I THINK IT RELATES TO SOME OF
THE PRIORITIES THAT YOU RAISED
FOR YOUR ROOM.
>> YEAH, ROBUST BRONCHIECTASIS,
SORRY, I CAN'T SEE THE CHAT.
>> DO WE NEED A ROBUST CF
BRONCHIECTASIS OR GENERAL
BRONCHIECTASIS MODEL?
>> WELL, YOU KNOW, THE PIGS AND
FERRETS DEVELOP BRONCHIECTASIS.
THIS WAS DISCUSSED, IT'S
PROBABLY ON HERE SOMEWHERE IN
ONE OF THE LOWER LEVEL ONES.
IT'S HIGHLY COSTLY.
I MEAN, THE ANIMAL I SHOWED IN
MY PREVIOUS TALK THAT DEVELOPED
MUCOID PSEUDOMONAS WAS PRETTY
HEALTHY.
COEXISTING WITH EXTREMELY HIGH
TITERS OF BACTERIA IN THE LUNG,
THREE YEARS OLD, TAKEN OFF
MODULATORS EARLY IN LIFE, THREE
TO FOUR MONTHS OF AGE.
SO, THE MODELS ARE HERE.
I THINK IT'S A MATTER OF
FIGURING OUT HOW TO ACCELERATE
DISEASE PROCESS, WE'RE WORKING
WITH THAT IN THE FERRETS, BY
CO-HOUSING AND, YOU KNOW, THE
TRANSMISSION OF THESE BUGS THAT
COME IN A SERIES, AN ORDER THAT
DEVELOP THE STABLE COEXISTENCE
OF PSEUDOMONAS, AND THERE'S VERY
SIGNIFICANT INFLAMMATION IN LATE
STAGE DISEASE.
DAVID, I'M NOT SURE IF YOU WANT
TO COMMENT ABOUT SOMETHING, YOU
WERE IN THIS SESSION AS WELL.
OKAY.
>> ALL RIGHT.
WE'LL MOVE ON TO THE REPORT-OUT
FROM BREAKOUT 3, AND THEN AFTER
THIS WE'LL HAVE A GENERAL
DISCUSSION FROM EACH, COVERING
ALL OF THE TOPICS FROM EACH OF
THE ROOMS.
>> THANKS, I'LL BE TALKING ABOUT
OUR DISCUSSION IN BREAKOUT 3,
LUNG DISEASE ON HIGHLY EFFECTIVE
MODULATOR THERAPY, THE
DISCUSSION WITH GINA AND MANU.
WE BROKE THE DISCUSSION INTO
FOUR MAIN TOPICS, YOU CAN SEE
HERE.
WE TALKED ABOUT THEMES RELATED
TO EMERGING CHALLENGES WITH
KNOWN ORGANISMS, CHANGES IN
BACKGROUND AND MAINTENANCE
THERAPY, POST HIGHLY EFFECTIVE
MODULATOR TREATMENT.
WE TALKED ABOUT WHAT WE DO AND
DON'T KNOW ABOUT STARTING AND
STOPPING THERAPIES, AND WE
TALKED ABOUT IMPORTANT QUESTIONS
FOR UNDERSTANDING DAMAGED
EPITHELIAL CELLS FROM PATIENTS
WITH LONGSTANDING AIRWAY
DISEASE.
THERE WERE A NUMBER OF COMMON
THEMES THAT CAME UP ACROSS THESE
DIFFERENT TOPICS, AND SO WE
SUMMARIZED THE OVERALL
DISCUSSION TO A COUPLE DIFFERENT
THEMES.
THE FIRST GENERAL THEME WAS HOW
DO WE RETHINK OUR GENERAL
APPROACH TO MONITORING CF
DISEASE, AND MONITORING
INFECTION WAS A BIG PART OF THAT
DISCUSSION.
SO WE TALKED ABOUT THE DECREASE
IN SPUTUM PRODUCTION IN PEOPLE
WITH CF ON HIGHLY EFFECTIVE
MODULATORS, AND HOW DO WE GET
AROUND THAT, HOW DO WE DETECT CF
PATHOGENS AND OTHER POTENTIAL
INFECTIONS THAT MAY BE DISEASE
CAUSING, DO WE NEED TO DO MORE
BRONCHIOSCOPES, SWABS AND HOW WE
LIKELY NEED MORE DATA ON HOW TO
USE OP SWABS, HOME SPUTUM
COLLECTION, SPUTUM COLLECTION IN
GENERAL IN TERMS OF TIMING, HOW
OFTEN, WHAT TESTS IN SPUTUM, DO
WE NEED NEW MARKERS OF
INFECTION, NEW WAYS OF DEFECTING
INFECTION IN PEOPLE WITH CF.
WE TALKED ABOUT UNDER THE THEME
OF HOW TO MONITOR CF DISEASE DO
WE NEED NOVEL WAYS OF MONITORING
LUNG DISEASE THAT SPIROMETRY
WILL BE IMPORTANT WAYS TO
MONITOR BUT NOT AS SENSITIVE AS
OTHER THINGS.
DO WE NEED NEW IMAGING
APPROACHES SUCH AS MRI, MORE USE
OF LCI, DO WE NEED WAYS TO DO
MORE MONITORING OF INFLAMMATION
OF OVER TIME, POTENTIALLY
GENERALLY DISCUSSION AROUND
NOVEL WAYS AND MORE SENSITIVE
WAYS TO MONITOR CF LUNG DISEASE
GOING FORWARD.
SECOND BIG TOPIC, HOW DO WE
ASSESS CF THERAPIES, THIS
RELATED TO CHANGES IN
MAINTENANCE THERAPIES, AND ALSO
HOW WE SHOULD BE USING THERAPIES
IN PEOPLE WITH CF.
A LOT OF THIS CONVERSATION WAS
AROUND KIDS, AND WHEN KIDS ARE
GOING TO BE STARTING HIGHLY
EFFECTIVE MODULATORS EARLY IN
LIFE, HOW DO WE DETERMINE WHEN
TO START THE DAILY THERAPIES,
THIS INCLUDED MUCOLYTICS,
DECISIONS IN TERMS OF WHAT ARE
THEY GOING TO BENEFIT VERSUS
MORE BURDEN WITH MINIMAL BENEFIT
IN DAILY THERAPIES.
WE TALKED ABOUT FURTHER DOWN THE
LUNG DISEASE SPECTRUM, SIMILAR
QUESTIONS REGARDING USE OF DAILY
THERAPIES, MUCOLYTICS, AND HOW
DO WE DETERMINE WHEN TO
CONTINUE, WHEN TO USE AS NEEDED,
WILL DIFFERENCES HELP DETERMINE
RELATIVE BENEFIT SUCH AS
PATIENTS WITH DIFFERENT DEGREES
OF ESTABLISHED BRONCHIECTASIS
VERSUS DIFFERENT CHRONIC
INFECTIONS, WILL THEY
DIFFERENTIALLY BENEFIT.
AND MOVING BACK TO THE FIRST
POINT OF HOW DO WE MONITOR CF
LUNG DISEASE, WHAT WILL WE USE
TO DETERMINE WHICH OF THESE
THERAPIES WILL BE THE MOST
BENEFICIAL IN SHORT TERM WITH
ONGOING STUDIES BUT THEN OVER
THE LONGER TERM TOO TO MAKE SURE
WE'RE STILL KEEPING PEOPLE
HEALTHY BUT MINIMIZING BURDENS
OF CARE THAT MAYBE AREN'T AS
BENEFICIAL.
AND THEN THE THIRD BIG TOPIC
THAT WE WENT OVER WAS THE NEED
STILL FOR NEW APPROACHES TO
TREATING CF DISEASE, AND SO ONE
OF THE TOP POINTS WE DISCUSSED
WAS ONGOING NEED FOR NOVEL
ANTIMICROBIALS FOR MULTI-DRUG
RESISTANT INFECTIONS,
HIGHLIGHTED BY THE SPEAKER EARLY
BUT CONTINUED NEED FOR
DEVELOPMENT OF NEW APPROACHES TO
CF INFECTION TREATMENT, BUT ALSO
IN THE NEW THERAPEUTIC
APPROACHES TOPIC WE TALKED ABOUT
HOW CAN WE OPTIMIZE CURRENT
TREATMENT APPROACHES FOR
EXACERBATION, ANTIBIOTIC
TOXICITIES, NEED TO WORK TOWARDS
REDUCING ANTIBIOTIC BURDEN AND
REDUCING ANTIBIOTIC TOXICITY
WITH EXACERBATION TREATMENT.
WE TALKED ABOUT ONGOING NEEDS TO
DEVELOP IMPROVED TREATMENT
APPROACHES FOR FUNGAL INFECTION,
DETERMINING OTHER INFECTIONS.
HOW DO WE TREAT, WHEN DO WE
TREAT, HOW DO WE HELP OPTIMIZE
OUTCOMES.
THOSE WERE THE HIGH POINTS THAT
WE HAD HERE.
MANU OR GINA, ANYTHING ELSE TO
ADD TO THE DISCUSSION ON THIS?
>> NO, THAT WAS GREAT.
ONE THING I WOULD ADD IS THAT
FOR NOVEL MICROBIALS, THE TOPIC
OF FINDING NEWER BETTER
TOLERATED NTM THERAPIES WAS ALSO
BROUGHT UP BY A COUPLE PEOPLE.
>> YEAH, THE ONLY THING TO ADD,
JUST TO PIGGYBACK WHAT LINDSAY
MENTIONED, WE TALKED ABOUT
WHETHER OR NOT THIS WAS
MENTIONED EARLY ON, BY J.P.,
ABOUT RETHINKING BECAUSE A LOT
OF SYMPTOMATIC THERAPIES WERE --
LIKE EFFICACY WAS TESTED IN THE
SETTING OF LIKE PRE-MODULATORS,
SO WHETHER OR NOT WE REALLY EVEN
SHOULD BE CONSIDERING CLINICAL
TRIALS IN PEOPLE WITH CF WITH
MODULATORS FOR SOME OF THESE
EXISTING APPROVED THERAPIES.
EVERYTHING ELSE WAS SUMMARIZED
NICELY BY LINDSAY.
>> WE'LL MOVE INTO THE GENERAL
DISCUSSION.
SO WE'LL OPEN UP THE BOARD THAT
HAS THE TOP-VOTED TOPICS FROM
EACH OF THE ROOMS.
AND SO I WOULD INVITE OUR
WORKSHOP CO-CHAIRS TO HELP
MODERATE THE DISCUSSION HERE AND
DISCUSS SOME TOPICS THAT
HARMONIZED ACROSS SOME OF THE
BREAKOUTS OR MAY BE DIFFERENT,
AND ALSO YOU CAN SEE IN THE
PARENTHESES HERE HOW MANY VOTES
EACH OF THE TOPICS GOT.
WE WILL ALSO BE MONITORING THE
CHAT AS WELL, IF OTHERS WANT TO
ASK QUESTIONS OR GIVE FEEDBACK
AS WELL.
>> I'LL START AND OPEN A
QUESTION TO THE ENTIRE AUDIENCE
HERE.
FROM THE CONTEXT OF THE ANIMAL
MODELS SECTION, WHAT ARE THE
KNOWLEDGE GAPS OR PHENOTYPES OR
BIOMARKERS ASSOCIATED WITH
PARTICULAR DISEASE STATES THAT
WOULD BE MOST USEFUL CLINICALLY
TO CF PATIENTS?
AND THEIR CAREGIVERS?
MARRAH, I ASSUME ANYBODY IN THE
AUDIENCE CAN TALK, RIGHT?
>> NO.
SO, I THINK THAT IF YOU'RE IN
THE MAIN DISCUSSION, MAIN
PARTICIPANTS, YOU WOULD USE THE
CHAT.
BUT ANY OF OUR PANEL TESTS FROM
TODAY ARE WELCOME TO WEIGH IN.
>> I HATE TO INTERRUPT.
THE FUNCTION TO SPEAK.
>> THEY CAN CHAT.
>> WE'RE SEEING THE LEAST VOTED
CATEGORY.
>> WE CAN'T UP-SORT THESE.
>> CAN YOU ROLL THE SCREEN?
>> THIS IS IT.
WE PULLED OUT THE TOP CATEGORIES
FROM EACH OF THE ROOMS.
YOU'RE SEEING THE ENTIRETY OF
THEM.
WE CAN'T SORT BY VOTES BECAUSE
THE FOURTH BOARD DOESN'T HAVE
THE VOTES, IT JUST HAS THE VOTES
THAT CAME FROM THE MAIN ROOM, IN
PARENTHESES.
THESE WERE PULLED FROM EACH OF
THE BREAKOUT ROOMS.
SO WE HAVE SESSION 1 ON THE
LEFT, ANIMAL MODELS IS 2 IN THE
MIDDLE, THE THIRD IS LUNG
DISEASE IN THE THIRD COLUMN.
>> FELIX, DO YOU WANT TO SPEAK
UP?
ARE YOU ABLE TO UNMUTE?
>> YOU USUALLY AM ABLE TO SPEAK
UP BUT I DON'T THINK I CAN DO IT
RYE NOW.
>> YOU'RE ON.
WE CAN HEAR YOU.
>> THANK YOU.
JUST BECAUSE JOHN WAS ASKING
THIS QUESTION, WE HAVE THIS
DISCUSSION IN THE FIRST SESSION
ABOUT PRE-CLINICAL MODELS FOR
INFLAMMATION.
J.P. ALSO BROUGHT THIS UP
BECAUSE WE REALLY LACK RELIABLE
MODELS.
AND IF ONE OF THE -- HOPEFULLY
MORE AFFORDABLE ANIMAL MODELS
COULD REPRESENT THAT RELIABLY
THAT WOULD BE VERY HELPFUL FOR
THE PRE-CLINICAL DEVELOPMENT OF
ANTI-INFLAMMATORY THERAPIES.
>> I'LL ADD.
EXACERBATIONS ARE DIFFERENT WITH
PEOPLE ON MODULATORS NOW, BUT
THERE'S SEVERAL TIMES OF
INFLAMMATIONS WE THINK ABOUT.
THERE'S THE BASELINE SMOLDERING
INFLAMMATION, EXACERBATION ADDS
ANOTHER WRINKLE HARD TO MODEL IN
ANIMALS BUT THAT WOULD BE AMAZE
FIGURE WE COULD DO THAT.
AND THEN AS WE DISCUSSED IN
GROUP 3, UNDERSTANDING WHAT AN
EXACERBATION IS, PREDICTING IT
IN THIS ERA, YOU KNOW, THAT
WOULD BE A GOOD REASON TO HAVE
THAT KIND OF MODEL BUT I'M NOT
SURE HOW WE ACHIEVE THAT WAXING
AND WANING IN AN ANIMAL MODEL.
>> , YEAH THERE'S ANOTHER
COMMENT THAT ECHOES THAT IN THE
CHAT.
YOU KNOW, THINKING ABOUT HOW TO
USE ANIMAL MODELS TO ASSESS
DISEASE IN CLINICALLY RELEVANT
WAYS SO WE'RE GOING TO HAVE A
SESSION ON SOME OF THE ENDPOINTS
AND SOME OF THE THINGS LISTED IN
THERE, IN THE CHAT, LIKE
NON-CULTURE-BASED OP SWABS,
URINE, THINGS LIKE THAT.
HOW WE WOULD USE THE ANIMAL
MODELS TO VALIDATE SOME OF THOSE
AND THEN TRANSLATE THOSE INTO
THE CLINIC, I THINK THAT'S WHAT
THAT COMMENT IS REFLECTING.
>> SO, FELIX, WE DO HAVE CF
ANIMAL MODELS, MULTIPLE ONES
THAT INDEX INFLAMMATION,
BRONCHIECTASIS, CHRONIC
LONG-TERM PERMANENT
COLONIZATION.
YOU KNOW, THE FERRET, THE PIG
BOTH DO.
THEY HAVE CHALLENGES, THEY ARE
MORE EXPENSIVE.
SUE BURKETT HAS THE RAT MODEL
THAT GETS MUCUS OBSTRUCTION.
SHE COULD COMMENT ON THE -- I
CAN'T REMEMBER THE INFLAMMATORY
STATE, BUT EVEN THE MOUSE MODELS
HAVE SOME ELEVATED INFLAMMATION
THAT MIGHT BE IN THE LUNG WHEN
CHALLENGED.
IT'S RELATIVE.
IF YOU WANT AN ANIMAL MODEL THAT
YOU'RE GOING TO BE ABLE TO RUN A
SMALL ANIMAL CLINICAL STUDY, FOR
EXAMPLE, THAT YOU WANT TO DO IN
HUMANS, WITH THE VERY CLOSE
DISEASE STATE TO WHAT IS SEEN IN
HUMANS, THEN, YOU KNOW, YOU HAVE
TO PICK THE RIGHT STATE OF
DISEASE, IF THAT'S CHRONIC
PSEUDOMONAS OR WHATEVER IT MIGHT
BE.
BUT THEY ARE AVAILABLE.
THEY ARE JUST EXPENSIVE, WHICH
IS ONE OF THE TOPICS THAT CAME
UP IN OUR -- IN THE ANIMAL MODEL
SECTION AS WELL.
>> I THINK THAT'S RIGHT, JOHN.
I THINK WE HAVE A LOT OF MODELS
THAT CAN ANSWER THE QUESTION, IF
THE EXPERIMENT IS DESIGNED THE
RIGHT WAY.
AND WHAT WE WOULD NEED IS HELP
FROM THE CLINICIANS TO LOOK
EXACTLY WHEN IS IMPORTANT AND IN
WHAT CONTEXT IS IMPORTANT.
>> SOUNDED TO ME THE RAT MODEL
HAS SOME ADVANTAGES OF BEING A
BIT MORE EXPOUNDABLE IN TERMS OF
NUMBER OF ANIMALS AND COSTS
ASSOCIATED WITH THAT.
SO, IT WOULD JUST BE NICE TO DO
THAT WITH AN ANTI-INFLAMMATORY
THERAPY THAT WE THINK OR KNOW
WOULD WORK, TO SEE THAT IT
ACTUALLY RECAPITULATES WHAT
COULD BE SEEN IN HUMANS BECAUSE
THIS IS ALWAYS THE DISCUSSION
ANTI-INFLAMMATORY DEVELOPMENT
CURRENTLY WE DON'T REALLY HAVE A
GOOD PRE-CLINICAL MODEL THAT WE
COULD RELY ON, EVEN THOUGH THERE
ARE ANIMAL MODELS, THEY HAVEN'T
BEEN UTILIZED IN ANY OF THESE
SETTINGS BEFORE, BUT I DON'T
WANT TO DOMINATE THE DISCUSSION
ANYMORE WITH THAT.
>> YEAH, I MIGHT JUST WANT TO
ADD THAT IT'S MUCH MORE
SIMPLIFIED MODEL IN VITRO
PERSONALIZED MEDICINE MODEL THAT
WE HAD ALSO A VERY HOT TOPIC
CREATING MODELS OF INFLAMMATION
IN VARIOUS REGARDS BECAUSE IT'S
A MORE COMPLEX MODEL THAT
REPRESENTS THE CF AIRWAY
EPITHELIA AND WOULD ALLOW TO
STUDY VARIOUS THERAPEUTICS,
ANTI-INFLAMMATORY STIMULI OR
CONDITIONS.
IT'S NOT AS SOPHISTICATED AS
ANIMAL MODEL BUT I THOUGHT I
WOULD ADD IT BECAUSE IT WAS A
BIG HOT TOPIC OF DISCUSSION.
>> IF I COULD COMMENT ON THAT, I
FIND ORGAN ON A CHIP
FASCINATING.
IN OUR SESSION, THE MULTI-ORGAN
NATURE OF THE DISEASE CAME UP
WHICH IS GOING TO BE DIFFERENT
BETWEEN THE DIFFERENT ANIMAL
MODELS IF THEY DON'T HAVE
PANCREATIC DISEASE OR DON'T
DEVELOP SPONTANEOUS LUNG
DISEASE.
BUT UNDERSTANDING THE
INTERACTIONS BETWEEN STATES THAT
ARE NOT FULLY PROTECTED ON
HIGHLY AFFECTED MODULATORS,
INTERACTIONS BETWEEN EPITHELIUM,
FOR EXAMPLE, LIKE HOW DOES THE
PANCREATITIS AFFECT COLONIZATION
IN THE LUNG, WE KNOW THOSE
PATIENTS DO WORSE IF THEY GET
CFRD.
AND SO BACK TO FELIX'S COMMENT,
I THINK, YOU KNOW, THERE ARE A
LOT OF MODELS HERE.
YOU START WITH THE ONE THAT
GIVERS YOU MAYBE THE BROADEST
DIRECTION AND WHERE YOU WANT TO
GO, MAYBE THAT'S LUNG ON A CHIP,
MOVE TO MOUSE OR RAT, AND THEN
THE CLOSER YOU GET TO FEELING
CONFIDENT ABOUT THE DRUG YOU'RE
GOING TO DEVELOP YOU PULL THE
TRIGGER AND DECIDE, YOU KNOW, DO
YOU HAVE TO GO INTO ONE OF THESE
MORE EXPENSIVE MODELS, AND TO
EVALUATE IT PRIOR TO CONVINCING
YOURSELF THAT IT'S TIME FOR A
CLINICAL TRIAL.
AT LEAST THAT'S HOW THE
INTERACTIONS THAT WE HAVE AT
IOWA WITH COMPANIES AND ACADEMIC
GROUPS THAT WANT TO USE THE
FERRET MODEL.
>> THERE'S A NUMBER OF COMMENTS
IN THE CHAT ABOUT OTHER WAYS
THESE KIND OF MODELS CAN BE
USED, CONTINUING ON THE THEME OF
EVEN JUST LOOKING FOR
ANTI-INFLAMMATORIES, ONE OF THE
ANIMAL MODELS COULD HELP US
LOOKING AT SIDE EFFECT,
OFF-TARGET EFFECTS WE MIGHT NOT
BE EXPECTING.
THE OTHER THING ESZTER BROUGHT
UP, I WILL BACK THIS UP, I THINK
THAT FOR -- IN A PETRI DISH WE
HAVE GOOD MODELS FOR
ANTI-INFLAMMATORIES BUT FOR
HUMANS VIEWING FV-1, AND CRP AND
BIOMARKERS.
AZITHROMYCIN, THE WORKHORSE,
DECREASED EXACERBATION, ESZTER
BRINGS UP AN ANIMAL MODEL WE
COULD COME UP WITH NOVEL
BIOMARKERS THAT WE COULD LOOK
FOR IN HUMANS THAT MIGHT BE MORE
PREDICTIVE OF LONG-TERM BENEFIT
OF ANTI-INFLAMMATORY AS A BETTER
BIOMARKER AND SO USING AN ANIMAL
MODEL THAT WAY TO HELP US WITH
OUR HUMAN CLINICAL TRIALS AS AN
ENDPOINT GENERATOR.
>> GOOD POINT.
>> THERE'S ALSO A LOT OF
COMMENTS IN HERE IN THE CHATTELS
ABOUT THE UTILITY OF USING THESE
MODELS TO ADDRESS THE OTHER 10%,
HOW WE COULD USE THEM FOR GENE
THERAPIES, LOOKING AT A COMMENT
HERE BY STEVE IS OFF TARGET
EFFECTS AND, YOU KNOW,
DIFFERENTIAL CFTR EXPRESSION
AFTER GENE THERAPY, IN DIFFERENT
ORGANS, AND POTENTIALLY OTHER
COMMENTS HERE ABOUT, YOU KNOW,
REALLY THINKING ABOUT HOW THE
MODELS CAN TRANSLATE INTO
CLINIC.
AND ANOTHER COMMENT WAS RAISED
HERE THAT MODULATORS DIDN'T
NECESSARILY NEED MODELS TO BE
DEVELOPED, AND SO MAYBE WE WON'T
BE USING ANIMALS IN THAT WAY TO
DEVELOP NEW DRUGS NECESSARILY,
BUT MIGHT BE OF MORE UTILITY FOR
ANTI-INFLAMMATORIES,
ANTIBIOTICS, AND POTENTIALLY
GENE THERAPIES.
>> THOSE ARE GOOD POINTS.
IN THE ANIMAL MODEL SECTION WE
TALKED ABOUT THE VIRAL TROPISM
AND HOW TO BETTER DETERMINE, YOU
KNOW, IF YOU'RE USING A VIRUS TO
DO GENE THERAPY, BETTER
DETERMINE WHAT WILL REPRESENT
THAT TROPISM IN HUMANS.
AND TO DATE, THAT'S GOING TO
INVOLVE MULTIPLE -- THE MORE
SPECIES YOU HAVE, THAT YOU CAN
TEST YOUR VIRUS IN, IT GOES TO
THE RIGHT CELL TYPES, AND THEN
YOU TEST IT IN A DISEASE STATE
AND REVERSES DISEASE IT'S GOING
TO HAVE HIGHER LOOKLY HOOD OF --
LIKELIHOOD OF WORKING IN HUMANS.
IS THERE A WAY TO DO THAT WITH
LUNG ON A CHIP?
YOU KNOW, WHERE YOU GOT ALL THE
MODELS ON THE PLATE TO TEST YOUR
THERAPY, AND YOU EVOLVE VIRUSES
THAT, YOU KNOW, ACROSS MULTIPLE
SPECIES AT ONCE, INTERESTING TO
THINK ABOUT.
>> ONE OF THE THINGS THAT CAME
UP IN OUR SECTION WAS ALSO WHAT
ARE THE RIGHT CELL TYPES TO BE
TARGETING, BECAUSE IF WE JUST
HAVE A PATIENT-DERIVED SYSTEM
LIKE ORGANOID IS THAT GOOD
ENOUGH FOR ANY OF THE GENE
THERAPY OR ANY OF THE -- WOULD
IT MIMIC WHAT HAPPENS IN AN
ANIMAL MODEL?
THAT WAS THE QUESTION THAT WAS
BEING ASKED.
>> YEAH, I MEAN, PROBABLY NOT,
UNTIL YOU TEST IT AND SHOW THAT
IT DOES THE SAME THING IN VIVO.
BUT IT'S ESPECIALLY TRUE FOR
ANYTHING THAT'S A VIRUS THAT HAS
A RECEPTOR THAT HAS TO BE
CONSERVED.
EITHER ACROSS SPECIES OR WITH
THE CELL PHENOTYPE.
>> WE HAVE TWO OTHER BREAKOUT
SESSIONS THAT HAPPENED, BEFORE
WE RUN OUT OF TIME.
DOES ANYONE WANT TO CHIME IN
ABOUT THE TOPICS FROM EITHER OF
THE OTHER BREAKOUT SESSIONS TO
DISCUSS?
>> I MIGHT CALL YOUR ATTENTION
TO ONE COMMENT THAT FELIX RAISES
IN THE CHAT THAT HE SAID THAT
FOR THE LUNG DISEASE SECTION, IT
WAS INTERESTING THAT THERE WAS A
FOCUS ON EARLY DISEASE.
BUT WHAT WAS THE DISCUSSION ON
ASSESSING THE REVERSIBILITY OF
MORE ADVANCED DISEASE?
IF SOMEONE FROM THAT SESSION,
THE LUNG SESSION, BREAKOUT 3,
COULD DISCUSS THAT QUESTION?
>> GO AHEAD, GINA.
>> I WAS GOING TO SAY WE DIDN'T
SPECIFICALLY TALK ABOUT THE TERM
"REVERSIBILITY" BUT ABOUT
TREATING AND MODERATING
ESTABLISHED DISEASE,
ANTICIPATING FOR INDIVIDUALS
WITH THIS ESTABLISHED DISEASE.
BUT WE DIDN'T -- I MEAN MY
CO-CHAIRS COULD CHIME IN BUT WE
DIDN'T TALK ABOUT REVERSIBILITY
PER SE.
WE DID TALK ABOUT STOPPAGE OF
THERAPIES, WHEN THAT SHOULD BE
CONSIDERED IN BOTH THE EARLY
LUNG DISEASE AND THE ADVANCED
LUNG DISEASE POPULATIONS, OR IN
MORE SIMPLER TERMS THE PEDIATRIC
AND ADULT POPULATIONS.
SO I JUST OPENED THAT UP TO MY
CO-MODERATORS TO COMMENT TOO.
>> YOU KNOW, ONE OF THE THINGS
THAT CAME THROUGH FOR US IS THAT
FED-1 MAY NOT BE AS SENSITIVE A
MARKER AND THERE WAS DISCUSSION
ABOUT LOOKING AT OTHER WAYS TO
ASSESS LUNG HEALTH.
YOU KNOW, MOSTLY THE CONTEXT OF
ASSESSING PROGRESSION OF DISEASE
, IN THE CONTEXT OF MAYBE FED-1
WOULDN'T NECESSARILY REFLECT
PROGRESSION, THINGS COULD GET
WORSE.
CERTAINLY ALONG THAT DISCUSSION
IF THINGS GOT BETTER, WHATEVER
WORK WE DID IN TERMS OF
IDENTIFYING OTHER OUTCOMES COULD
ALSO BE USED TO SEE HOW IT'S
REVERSIBLE IT IS, WHETHER
IMAGING OR OTHER TYPES OF
MODALITIES.
LOOKING AT OTHER OUTCOMES IS AN
IMPORTANT OUTCOME TO GO FORWARD.
>> THANKS, THAT HELPS IN MY TALK
TOMORROW ON THESE TOPICS.
>> I THINK ALSO I MIGHT CALL
ATTENTION TO SOMETHING THAT
MARTINA PUTS IN THE CHAT ABOUT
THE COMPLEXITY OF THESE MODELS
AND THINKING ABOUT BRINGING IN
DIFFERENT TEAMS OF EXPERTISE.
SHE NOTES IN THERE EPITHELIAL
BIOLOGISTS, INFLAMMATION
EXPERTS, BIOINFORMATICS EXPERTS,
ET CETERA.
SO I GUESS MY QUESTION TO THE
GROUP IS, ARE SOME OF THESE
AREAS THAT YOU BROUGHT UP, IS
THERE A GAP IN THE TYPE OF TEAM
SCIENCE THAT WE COULD BE
SUPPORTING OR SOLICITING OR
THINKING ABOUT MORE CREATIVELY
TO MOVE SOME OF THESE AREAS
FORWARD?
I KNOW THIS IS A VERY TIGHT
CLOSE COMMUNITY, BUT THAT
PARTICULAR COMMENT, YOU KNOW,
RAISED TO ME, THAT QUESTION OF
WHAT YOU THINK ABOUT TEAM
SCIENCE AND HOW WE MIGHT BE ABLE
TO SUPPORT THAT.
>> I'LL MAKE ONE COMMENT.
THIS DID COME UP IN THE ANIMAL
MODEL SECTION, IT WAS ABOUT HOW
REALLY MOST OF THE MODELS, NOT
PROBABLY ALL, EXCEPT FOR THE
MOUSE, MAYBE THE RAT TOO, YOU
KNOW, ARE AN ORPHAN GENOME.
IN THIS DAY AND AGE, FULLY
TAPPING THE OMICS TECHNOLOGIES
TO UNDERSTAND THE DISEASE STATE
IS -- THERE'S SO MUCH POTENTIAL.
BUT THE LIMITATION IS HAVING A
REALLY ACCURATE GENOME.
WE STRUGGLE WITH THIS IN THE
FERRET.
BUT IT NEEDS TO HAVE MONEY
THROWN AT IT TO COMPLETE IT, AND
GET ALTERNATIVE SPLICE FORMS,
ORTHOLOGS, YOU KNOW, ANNOTATED
CORRECTLY.
>> YEAH, I WANTED TO REALLY PUT
THE IMPORTANCE ON INTERACTION OF
DIFFERENT EXPERTS FOR THE
COMPLEX MODELS, WHAT MARRAH JUST
SAID, EPITHELIAL BIOLOGISTS,
THINKING ABOUT OTHERS THAT KNOW
MORE ABOUT NEUTROPHILS AND
INFLAMMATION, SINGLE CELL DATA,
BIOINFORMATICS, BIOENGINEERS.
BESIDES THAT IT CAME ALSO
CLEARLY TO THE SURFACE THAT EVEN
INTERACTION BETWEEN THE BASIC
RESEARCHERS THAT USE IN VITRO
MODELS AND OTHERS THAT USE
ANIMAL MODELS WOULD BE VERY
IMPORTANT.
THERE WAS A COMMENT I THINK BY
J.P. SAID ANIMAL MODEL OUTCOMES
AND IN VITRO MODEL OUTCOMES
SHOULD BE COMPARABLE, EVEN MORE
REALLY THIS IS ONE OF OUR POINTS
HERE, HOW CAN LABORATORY
FINDINGS BE BETTER LEVERAGED TO
MOVE FROM PRE-CLINICAL STUDIES
TO THE CLINIC.
SO EVEN THE COLLABORATION OF
BASIC RESEARCHERS WITH
CLINICIANS WHICH IS ALREADY
HAPPENING A LOT BY OBTAINING THE
PRIMARY TISSUES FROM THE CLINIC
BUT THERE COULD BE EVEN MORE
COLLABORATION THAT CLINICAL
READOUTS ARE DIRECTLY CORRELATED
TO LABORATORY EVALUATIONS.
AND COLLABORATIONS BETWEEN
DIFFERENT EXPERTS IN CF
COMMUNITY WILL DEFINITELY MOVE
THE FIELD FORWARD IN MANY
REGARDS.
>> ANN, DID YOU WANT TO SAY
SOMETHING?
>> YEAH, WANTING TO SECOND WHAT
JOHN SAID ABOUT THE GENOMES.
I MEAN, IF WE COULD BRING IN A
LITTLE BIT MORE POWER ON
SEQUENCING, IN-DEPTH SEQUENCING,
GETTING A REALLY GOOD COMPLETE
MAP FOR SOME OF THE MODELS THAT
ARE RELEVANT TO CF, IT IS A
CHALLENGE.
IT TAKES MUCH LONGER THAN IT
NEEDS TO WHEN YOU DON'T HAVE A
COMPLETE GENOME, AND WE HAVE
SPOKEN TO NHGRI, I'M NOT SURE
ANY MODELS WE'RE TALKING ABOUT
HERE ARE TOP OF THEIR LIST.
>> I MIGHT RAISE ESZTER'S
COMMENT FROM THE CHAT AS WELL
FOR DISCUSSION.
SHE MENTIONS SENESCENCE AS SORT
OF A SIGNATURE THAT PERSISTS IN
THE EPITHELIUM DESPITE
CORRECTORS, AND THINKING ABOUT
SOME OF THE TALKS INCLUDING
FRANK'S EARLIER FROM TODAY OF
THESE SIGNATURES THAT REALLY
CAN'T BE CORRECTED, AND SO I
WONDER IF ANYBODY WANTS TO
DISCUSS THAT IN THE TYPE OF
RESEARCH GAPS AND OPPORTUNITIES
THAT THERE MIGHT BE THERE.
>> PROBABLY ONE THING I WOULD
ADD TO THAT IS THAT FOLKS WITH
CF WHO START CORRECTORS WITH
ESTABLISHED DISEASE PROBABLY
HAVE HAD THE EQUIVALENT OF AN
ENTIRE LIFESPAN-PLUS OF
INFLECTION, INFLAMMATION,
REPEATED INJURY, MOST -- YOU
KNOW, WHAT WE COULD NEVER
COUNTER IN OUR NORMAL LIVES.
THAT'S GOT TO LEAVE POTENTIALLY
SOME SORT OF EPIGENETIC LOAD OR
IRREVERSIBLE STRUCTURAL DAMAGE
THAT YOU CAN'T OVERCOME.
AND I THINK THAT TRANSCRIPTIONAL
SIGNATURES COULD BE REALLY
POWERFUL AT DETECTING THESE,
EVEN IF THERE ARE NECESSARILY
VERY OBVIOUS SIGNATURES LIKE
THERE ARE WITH BRONCHIECTASIS.
A LOT OF THESE MAY BE EARLY
PRECURSORS TO CHRONIC LUNG
DISEASES OF AGING THAT COULD
COME.
>> I AGREE.
I'LL JUST MAKE A COMMENT TO WHAT
YOU SAID TOO, MARRAH.
I COLLABORATE WITH FRANK, SO I
KNOW WHAT HE'S DOING.
AND, YOU KNOW, THE DISCOVERY OF
EPIGENETIC CHANGES IN THE STEM
CELL COMPARTMENTS OF THE LUNG IS
INCREDIBLY IMPORTANT TO GENE
THERAPY, GENE EDITING.
AND, YOU KNOW, I CAN'T SEE A
PATH TO TESTING A DRUG WITHOUT
IT FIRST GOING THROUGH THE
DISEASE MODEL.
YOU KNOW, EVEN IF YOU COULD
SPECIFICALLY REVERSE THAT
EPIGENETIC PROGRAMMING, THAT
PROGRAM IS SO IMPORTANT TO THE
BODY.
I MEAN, UNDERSTANDING OFF-TARGET
EFFECTS, IT'S GOING TO TAKE
ANIMAL MODELS THAT CAN WE
PRODUCE THE HUMAN PHENOTYPE
DISEASE MODELS TO GO IN AND TEST
AND MAKE SURE THAT THE DRUGS ARE
SAFE AND THEY DO WHAT YOU THINK
AND THEY KILL ONLY
PRO-INFLAMMATORY BASAL CELLS,
FOR EXAMPLE.
SO I THINK IT'S IMPORTANT.
>> I'M NOTICING ROBERT GRAY'S
COMMENT IMMUNOSENESCE AND
EPITHELIAL SENESCENCE ARE AREAS
TO FOCUS ON.
DO WE THINK POST-MODULATOR CF
AIRWAYS ARE THE SAME THING AS
NON-CF BRONCHIECTASIS?
OR DOES THE -- IN ADULT WITH CF,
WHO HAD CF FOR THE FIRST 25
YEARS OF THEIR LIFE AND START
MODULATORS ONCE THEY START
MODULATORS IS BRONCHIECTASIS
GOING TO BE FUNDAMENTALLY
DIFFERENT BECAUSE EPIGENETIC
CHANGES MAY HAVE HAPPENED?
OR IS THAT THE SAME THING THAT'S
HAPPENING IN NON-CF
BRONCHIECTASIS?
>> IT'S A GOOD POINT, PROBABLY
SOMEWHERE IN BETWEEN BECAUSE THE
CFTR MODULATORS ARE NOT 100%,
EVEN IF YOU'RE HETEROZYGOTE FOR
MUTATIONS, INCLUDING
PANCREATITIS, DIABETES, AND SO
ON.
>> I THINK THE UNDERSTANDING OF
REPAIRING THE LUNG AND
PREVENTING DAMAGE AND THE USE OF
ANIMAL MODELS FOR THAT IS VERY
USEFUL.
AS AN ADULT PROVIDER, I THINK
OF -- WHEN I THINK ABOUT WHAT'S
THE FUTURE ON PEOPLE WITH HEMT,
I'M JUST THINKING ABOUT THE
CONTINUED STATE OF THE AIRWAY,
SO ARE WE LOOKING FOR THE SAME
DRUGS AND TREATMENTS AS NON-CF
BRONCHIECTASIS OR IS THIS GOING
TO BE -- CONTINUE TO BE A UNIQUE
POPULATION BECAUSE OUR PATIENTS
ARE GOING TO BE LIVING LONGER,
WE'LL HAVE MORE ADULT PATIENTS,
AND WE'RE GOING TO HAVE A FAIRER
PROPORTION OF PATIENTS WITH
DAMAGED LUNGS, LIVING LONGER,
THAT WE'RE GOING TO HAVE TO
UNDERSTAND AND TREAT.
SO-- ROBERT, YOU SHOULD SPEAK
UP.
ROBERT GRAY.
CAN YOU EXPLAIN MORE CF PATIENTS
ON HEMT FOR ONE YEAR DON'T LOOK
LIKE NON-CF BRONCHIECTASIS ON
CAT SCAN?
OR IF ANYONE ELSE WANTS TO WEIGH
IN ON THAT?
>> CAN YOU HEAR ME?
>> YES, WE CAN.
>> SORRY, I'VE BEEN DEALING WITH
A VOMITING CHILD ALL DAY IN
SCOTLAND.
WE'VE BEEN DOING A LOT OF
OBSERVATIONAL EXPERIMENTS
LOOKING AT THESE PATIENTS.
WE'VE GOT TEN PATIENTS
COMPLETELY MODULATOR NAIVE THAT
WE LOOK PRE AND POST ONE YEAR
TRICAFTA AS WE CALL IT.
THE BRONCHIECTASIS LOOKS
DIFFERENT.
THEY HAVE DILATED AIRWAYS BUT
THEY LOST THE WALL THICKENING.
LOOKS LIKE A DIFFERENT PROSPECT
IN TERMS OF THE RADIOLOGY.
WHICH WE WERE NOT EXPECTING.
I WAS EXPECTING TO MAKE OUR
PATIENTS INTO NON-CF
BRONCHIECTASIS BUT APPEAR TO
HAVE MADE OUR PATIENTS WHO
COMPLETE THERAPIES INTO A
DIFFERENT CATEGORY.
A SHOUT OUT TO EX VIVO MODELS.
WE NEED TO GET MORE AMBITIOUS,
LOSS OF CO-CULTURE AND LOSS OF
BRINGING IN EXPERTISE BECAUSE WE
CAN DO SOME GOOD GOOD STUFF IN
EX VIVO MODELING.
I'LL BE QUITE NOW.
>> FRANK, DID YOU WANT TO SAY
SOMETHING?
>> I'M JUST LISTENING.
THERE IS SIGNIFICANT OVERLAP
BETWEEN VARIETIES IN COPD AND
CYSTIC FIBROSIS, YET TWO NEW
ONES THAT WE HAVEN'T SEEN.
THE COMPLETE GESTALT WILL BE
DISEASE SPECIFIC.
WHAT DOES AN EARLY STAGE LOOK
LIKE?
THIS IS WHAT THE ANIMAL MODEL
WILLS KEY.
ALSO CLINICAL EXPERIENCE NOW
GOING ON.
I THINK IT'S GOING TO BE
IMPORTANT TO WATCH.
>> MARRAH, THAT'S A GOOD
COMMENT, FRANK.
IF I COULD MAKE A COMMENT.
THERE'S BEEN A LOT OF ACTIVITY
ON RENAL DISEASE, AND
NEPHROTOXICITY AND STATING THIS
IS IT'S AN UNDER STUDIED AREA,
IMPORTANT IN THE FUTURE WITH
PATIENTS ON HEMT.
CAN ANYBODY -- I DIDN'T THINK
THERE WAS KIDNEY DISEASE IN CF
PATIENTS.
I FEEL UNINFORMED OTHER THE FACT
IT'S ANTIBIOTIC USAGE,
OFF-TARGET DRUG USAGE.
IS THERE SOMETHING THAT'S
FUNDAMENTAL TO THE LACK OF CFTR
IN THE KIDNEY THAT LEADS TO
DISEASE STATE?
FELIX OR SOMEBODY THAT'S A
CLINICIAN?
JEN?
>> CAN YOU HEAR ME?
>> THIS IS AGNES, A PRINCIPAL
INVESTIGATOR NEPHROLOGIST,
WATCHING THIS AREA TO DEVELOP.
CFTR IS EXPRESSING SEGMENTS, IT
HAS DEVELOPED -- IT IS POORLY
UNDERSTAND.
IT MUST HAVE HAVE A ROLE,
PRESENT IN THE KIDNEY.
MORE FOCUS ON UNDERSTANDING
DEVELOPMENTAL ROLE IN THE KIDNEY
WILL BE VERY IMPORTANT TO INFORM
WHAT TO EXPECT.
I THINK AS WE'RE GOING TO BE
AGED, WE CAN MODULATE.
>> FOR PATIENTS WITH DIFFERENT
MUTATIONS, WHO RESPOND
DIFFERENTLY TO MODULATORS OR WHO
MAY NOT BE ON MODULATORS, MAKING
SURE THAT WE'RE CAPTURING IT'S
RIGHT RESEARCH QUESTIONS FOR ALL
GROUPS, AND SO THAT COMMENT WAS
ALSO RAISED EARLIER, I'M GOING
TO READ THIS, IT'S DIFFICULT TO
COMPLETELY ADJUST SURVIVAL
MODELS FOR THIS PROBLEM.
BECAUSE IT TAKES TIME TO ACCRUE
THE DISEASE IN THE PHENOTYPE.
THINKING ABOUT ADDITIONAL GAPS
MOVING INTO DAY 2 WILL BE MORE
THAN, ADDING TO THE DISCUSSION
FOR TOMORROW.
SO I WANT TO THANK YOU ALL FOR
YOUR PARTICIPATION TODAY AND
LOOK FORWARD TO ANOTHER LIVELY
AND FULL DAY TOMORROW.