I'M WINN ARIAS AND WE WELCOME
YOU TO THE THIRD YEAR OF THE DE
DEMYSTIFYING MEDICINE AT THE
NATIONAL INSTITUTES OF HEALTH.
THIS IS TO BRIDGE THE EXCITING
DEVELOPMENTS IN BIOLOGY,
ENGINEERING AND COMPUTER
SCIENCES WITH MEDICINE.
THIS TAKES MANY FORMS.
WE HAVE REACHED THIS ISSUE IN
SPACE AT THE BOTTOM OF THE SEA
AND ORIGIN OF LIFE AND TODAY IN
A MORE TRADITIONAL WAY WE ARE
CONCERNED WITH A DISEASE DISEASE
AND THE BRIDGING IS BETWEEN THE
CLINICAL, THERAPEUTIC AND BASIC
UNDERLYING SCIENCE OF THE
DISEASE ITSELF.
DEMYSTIFYING MEDICINE MEETS
EVERY TUESDAY FROM 4:00 TO 6:00
FROM JANUARY TO THE MIDDLE OF
PAY.
-- MAY.
YOU CAN WATCH IT USING THE LINK
THAT'S PRESENT ON THE SLIDE THE
CME CREDIT WAS LISTED AS 52088
AND ENCOURAGE MANY IN THIS
COUNTRY AND ABROAD TO COMMIT
QUESTIONS CLICKING ON THE SEND
LIVE FEEDBACK ON YOUR COMPUTER
OR SEND IT BY VIDEOCAST.
I WOULD BRING YOUR ATTENTION TO
ALL PREVIOUS SESSIONS FOR THE
PAST 25 YEARS ARE ARCHIVED AND
THE LINK IS SHOWN HERE.
IF YOU HAVE ADDITIONAL QUESTIONS
GET IN TOUCH.
THE LOGO IS THE BROOKLYN BRIDGE
AND THE TWO PEOPLE ON THE
SIDEWALK OR CAT WALK ARE
DISCUSSING TWO DIFFERENT
ASPECTS, TWO SILOS, IF IT WERE.
SO TODAY THE SILOS ARE
REPRESENTED BY GENETIC AND
THERAPEUTIC ASPECT.
WE'RE EXTREMELY FORTUNATE TO
HAVE THREE PRESENTERS TODAY.
THE FIRST IS LESLIE GORDON A
PROFESSOR OF PEED RICKS AT THE
ALBERT MEDICAL SCHOOL AT BROWN
UNIVERSITY IN PROVIDENCE, RHODE
ISLAND.
SHE IS THE CO-FOUNDER AND
MEDICAL DIRECTOR OF THE RESEARCH
FOUNDATION.
SHE IS DESIGNED AND IMPLEMENTED
SEVERAL CLINICAL TRIALS FOR
PROGERIA WITH VARIOUS COLLEAGUES
IN BOSTON AND HAS DEVELOPED AN
OBJECTIVE CLINICAL BIOMEDICAL
THAT CAN BE USED TO ASSESS EYE
THERAPEUTIC RESPONSE.
HER SON, SAM BURNS WAS BORN IN
1998 WITH PRO GERRIA AND RECALL
YOUR ATTENTION TO A REMARKABLE
2013 TED TALK SHE PROVIDED.
OUR SECOND SPEAKER OR
PARTICIPANT IS WELL BUT A BRIEF
INTRODUCTION AND FRANCIS COLLINS
IS A GLOBAL LEADER RESEARCH AND
POLICY HE FOUND THE GENES FOR
CYSTIC FIBROSIS, NEURAL FIBR
FIBROMATOSIS AND CAME TO THE NIH
TO HEAD THE HUMAN GENOME PROJECT
WHICH BECAME THE HUMAN GENOME
RESEARCH INSTITUTE AT WHICH THE
HUMAN GENOME WAS SEQUENCED.
HE IS THE LONGER SERVING
DIRECTOR AT THE NIH FROM 2009 TO
2022 UNDER THREE PRESIDENTS.
HE'S INITIATED MAJOR PROJECTS
SOME OF WHICH ARE LISTED ON THE
SLIDE HERE.
THEY COVER FUNDAMENTAL SCIENCE
TO CLINICAL ASPECTS.
HE'S ALSO VERY ACTIVE IN THE
DEVELOPMENT OF GLOBAL PROGRAMS
PARTICULARLY RELATED TO HIV AND
MORE RECENTLY TO HEPATITIS C.
IN THE GOVERNMENT, HE'S BEEN THE
PRESIDENT'S ACTING SCIENCE
ADVISER AND CO-CHAIR WITH THE
SCIENCE TECHNOLOGY COUNCIL.
FRANCIS HAS BEEN AWARDED
ENUMERABLE PRIZES AND AWARDS FOR
HIS EXEMPLARY LEADERSHIP.
THE MOST NOTED ARE MEMBER OF THE
NATIONAL ACADEMY OF MEDICINE AND
SCIENCE AND NATIONAL MEDAL OF
FREEDOM AND NATIONAL MEDAL OF
SCIENCE AND ELECTED TO THE ROYAL
SOCIETY.
IN 2002 HE HAS BEEN WORKING EVEN
THROUGH THE PERIOD OF HIS NIH
LEADERSHIP SEARCHING FOR GENES
FOR DIABETES MELLITUS TYPE II
AND THE SUBJECT OF TODAY'S
DISCUSSION THE
HUTCHINSON-GILFORD SYNDROME
KNOWN AS PROGERIA.
THE TITLE IS PROGERIA A GENETIC
AND THERAPEUTIC ADVENTURE.
THE FIRST SPEAKER IS LESLIE.
>> THANK YOU FOR INVITING US FOR
THE TRIPLE TALK.
WE'RE SO EXCITED.
I DO WANT TO START BY
INTRODUCING ACTUALLY OUR THIRD
PRESENTER WHO HAS COME TO US
FROM ITALY ON ZOOM, SAMMY BASSO.
I'VE KNOWN SAMMY SINCE HE WAS 5
AND HE'LL TELL YOU HIS STORY AND
HE WAS VERY CLOSE WITH MY SON
SAM AND WE HAVE SORT OF GROWN
TOGETHER AS A FAMILY, OUR FAMILY
AND HIS FAMILY AND I CAN TELL
YOU THAT HE IS ONE OF THE MOST
REMARKABLE PEOPLE I HAVE EVER
KNOWN.
JUST AS ONE EXAMPLE, SAMMY WILL
TELL YOU HE HAS GROWN INTO
GETTING HIS ADVANCED DEGREE, HIS
MASTERS IN THE SCIENCES AND
GENETICS AND HE HAD TO GO FOR THAT FROM VENICE AREA AND TAKE A
TRAIN TO THE ROME AREA AND
BECAUSE IT TOOK SO LONG ON THE
TRAIN HE WROTE A BOOK.
AND THE BOOK IS THICK AND IT WAS
PUBLISHED.
THAT'S A TASTE OF WHAT SAMMY'S LIKE.
WHAT WE'RE GOING TO DO IS SHARE
OUR JOURNEY.
WE'RE GOING TO TELL YOU WHERE WE
ARE AND WHERE WE'RE GOING AND
WHERE WE'VE BEEN ON OUR ROAD TO
THE CURE FOR PROGERIA AND ALONG
THE WAY WE HOPE YOU CAN SEE HOW
OUR STORY CAN APPLY TO MILLIONS
AND MILLIONS OF PEOPLE.
WE'RE GOING TO SHARE OUR
PERSPECTIVE FROM THREE TYPES OF
INTERRELATED STAKEHOLDERS AND
GET TO THE PATIENT AND FAMILY
PERSPECTIVES, FOUNDATIONAL
PROGRAM BUILDING PERSPECTIVES
AND THE BASIC AND CLINICAL
SCIENTIFIC DISCOVERY PERSPECTIVE
AND THEY CANNOT BE MUTUALLY
EXCLUSIVE AND WE GO FROM SCIENCE
TO CHATTING AND INTERVIEWS IN
CHATS AND QUESTIONS OF EACH
OTHER AND SO PLEASE SEND IN YOUR
QUESTIONS BECAUSE WE MIGHT
ANSWER -- WE'RE GOING TO ANSWER
A FEW INTERSPERSED AND THEN
WE'LL GO BACK TO SCIENCE AND
THEN GO TO INTERVIEW.
IT SHOULD BE PRETTY FUN.
THIS IS WHO WE'RE FIGHTING FOR
AND MORE AND -- AND SOMETHING
I'M TALKING ABOUT MILLIONS OF
PEOPLE WHO HAVE RARE AND ULTRA
RARE DISEASES.
THERE ARE MORE THAN 7,000 OF
THEM AND WE LEARN FROM EACH
OTHER WHEN WE SUCCEED.
GET CALLS ALL TE TIME AND A CALL
PEOPLE ALL THE TIME WHO ARE
DEALING WITH MOSTLY ULTRA RARE
BUT RARE DISEASES AS WELL.
WE'RE TALKING ABOUT OVER 350
MILLION HUMAN BEINGS WHOSE LIVES
ARE AT STAKE AND MOST DISEASES
ARE GENETIC AND MOST CHILDREN
WITH RARE DISEASES WILL DIE BY
THE TIME THEY'RE 5.
PRETTY IMPACTFUL AND IMPACTS
THEIR LIVES AND THE LIVES OF
THEIR PARENTS, THEY'RE SIBLINGS
AND REVERBERATES THROUGH
FAMILIES AND COMMUNITIES.
OUR STORY IS ONE OF MILLIONS AND
WHEN WE SUCCEED I BELIEVE IT
WILL BE A SUCCESS AMONG MILLIONS
AS WELL.
WE JUST HAVE TO FIGURE OUT WHICH
CAMERA WORKS.
HI, SAMMY.
WE'RE COMING TO YOU.
>> THANK YOU.
THIS IS BEAUTIFUL RACHEL AND A
SEQUENCE OF RACHEL BORN AS A
TODDLER, SECOND GRADE AND THEN
JUST THE WEEK BEFORE SHE TURNED
10 WHEN SHE PASSED AWAY FROM
HEART FAILURE.
PROGERIA IS CALLED A SEGMENTAL
PREMATURE AGING DISEASE.
IT'S NOT PASSED DOWN IN
FAMILIES.
IT'S AUTOSOMAL DOMINANT,
SPORADIC AND CHILDREN WITH
PROGERIA DIE AT THE AVERAGE AGE
OF 14 1/2 BUT THERE'S A WIDE
RANGE AND THEY DIE OF PREMATURE
ATHEROSCLEROSIS WHICH IS THE
SAME DISEASE WHICH AFFECTS THE
REST OF US IN OUR '60s, '70s,
'80s AND '90s BUT HAPPENS FAST.
IT AFFECTS OTHER BODY SYSTEMS
AND IT'S IMPORTANT TO UNDERSTAND
NOT ONLY THE CLINICAL NATURAL
HISTORY OF THAT BUT WHAT THAT
MEANS BIO LOGICALLY ESPECIALLY
WHEN YOU'RE TRYING TO FIND
TREATMENTS AND CURE.
THERE IS LOSS OF HAIR.
THE CHILDREN ARE BORN LOOKING
NORMAL BUT HAVE FAILURE TO
THRIVE WHICH ARE LIFE LONG AND
VERY SMALL.
THERE'S A LOSS OF SUB CUTANEOUS
BODY FAT AND BONY CONSEQUENCES.
JOINT CONTRACT JURES.
-- CONTRACTURES AND MOST
IMPORTANTLY YOU'VE GOT THE
CARDIOVASCULAR DISEASE AND HERE
I'M SHOWING YOU WHAT THAT LOOKS
LIKE.
THIS IS SHOWING YOU THE CAROTID
ARTERIES, BLOOD FLOWING UP FROM
THE BRAIN OVER HERE AND
COMPLETELY BLOCKED ON THE RIGHT
AND DOWN THE CONSEQUENCES OF
THAT THE WHITE AREA IS SHOWING
STROKE.
HERE YOU'RE SEEING THE CROSS
SECTION OF THE AORTA.
ALL OF THIS IS PLAQUE.
IT'S HUGE.
THIS IS A LAYER SUPPOSED TO BE
SUPER THIN MAKING FOR STIFF
VASCULATURE AS IT'S STIFF WHEN
IT'S TRYING TO PUSH BLOOD
AGAINST IT AND A CT SCAN OF A
15-YEAR-OLD WITH PROGERIA AND
ALL THIS WHITE IS CALCIUM.
THIS IS THE AORTIC ARCH AND
DESCENDING AORTA AND DOES NOT
LOOK GOOD.
THIS IS WHAT WE'RE UP AGAINST.
I'LL TELL YOU A STORY THAT IS
VERY COMMON TO VERY RARE
DISEASES.
WHEN SAM WAS 2 AND DIAGNOSED IN
1998 I HAD NEVER HEARD OF
PROGERIA AT ALL OR TAUGHT ABOUT
IT IN MEDICAL SCHOOL.
THERE WERE ONLY A COUPLE
SCIENTISTS WORKING AT ALL
THROUGHOUT THE WORLD IN PROGERIA
AND THERE WAS NOTHING OUT THERE.
NO FUNDING, WE DIDN'T KNOW FIT
WAS A GENETIC DISEASE, HOW TO
TREAT IT, THE NATURAL HISTORY.
THERE WAS NO PLACE FOR FAMILIES
AND PHYSICIAN TO GO.
NO PLACE FOR TO US GO.
AND THIS IS ESPECIALLY BACK THEN
A VERY COMMON STORY.
AND FAMILIES WOULD TAKE ACTION
AND THEY WOULD CREATE NOT FOR
PROFITS AND TRY TO GET SOMETHING
MOVING IN THIS FIELD TO HELP
THEIR CHILD AND OTHERS AND
THAT'S WHAT WE DID.
WE CREATED THE PROGERIA RESEARCH
FOUNDATION.
MY HUSBAND AND SISTER AUDREY AND
I STARTED A FOUNDATION IN 1999 A
FEW MONTHS AFTER SAM WAS
DIAGNOSED TO FIND THE CAUSE,
TREATMENT AND CURE FOR PROGERIA.
AND THAT'S IT.
VERY CLEAN, CLEAR AND FOCUSSED.
WE HAD TO START FROM SCRATCH.
WHAT DID WE DO?
WE STARTED WITH PATIENTS AND
STARTED BY SAYING WHAT IS NEEDED
AND NOT THERE AND WHAT WILL GET
SOMETHING MOVING?
SO WE CREATED AN INTERNATIONAL
PROGERIA REGISTRY AND WHAT WE'RE
ALL GOING TO TRY TO DO IS SHOW
YOU HOW THESE AND OTHER THINGS
BUILD TO SUCCESS OVER TIME.
THE THINGS YOU DON'T HEAR ABOUT.
THE INTERNATIONAL REGISTRY,
MEDICAL AND RESEARCH DATABASE TO
UNDERSTAND THE NATURAL HISTORY
OF DISEASE FROM CLINICAL BANK
THAT SELL BLOOD AND TISSUES AND
BLOOD COMPONENTS TO RESEARCHERS
AROUND THE WORLD AND THE SEARCH
FOR THE GINA ASSUMING THIS WAS A
GENETIC DISEASE OR AT LEAST WE
DID WHEN WE APPROACHED FRANCIS
WE THOUGHT IT MIGHT BE.
WE WEREN'T SURE.
THAT'S THE SPRING BOARD.
THERE'S OTHER THINGS.
THERE'S AN AMAZING CADRE OF
VOLUNTEERS WHO DO LOTS AND LOTS
OF THINGS OF COURSE.
OUR MEDICAL RESEARCH COMMITTEE
AND GRANTS PROGRAM AND WORKSHOPS
TRYING TO SAY HOW DO WE BRIDGE
OUR WORKSHOPS AND SCIENTIFIC
MEETINGS BRINGING TOGETHER THE
PATIENTS, CLINICIANS AND BASIC
SCIENTISTS AND THEY SOMETIMES
DON'T KNOW HOW TO TALK TO EACH
OTHER BUT OVER THREE DAYS EVERY
OTHER YEAR THEY FIND A WAY AND
THEN THEY COLLABORATE AND IT'S
BEEN WONDERFUL.
I'M GOING TO TURN IT OVER NOW TO
SAMMY WHO IS GOING TO TALK A
LITTLE BIT ABOUT HIS LIFE
GROWING UP AND SINCE HE HAS A
MEMORY LIKE I CANNOT BELIEVE,
EVERYTHING HE'S GOING SHARE WITH
YOU STARTS PRETTY YOUNG AND GOES
THROUGH TODAY.
SAMMY, TAKE IT AWAY.
>> THANK YOU.
THANK YOU SO MUCH.
I REMEMBER VERY WELL THAT MOMENT
IN WHICH THAT PICTURE WAS SHOT
AND WE WERE PLAYING TOGETHER.
IT WAS THE FIRST TIME I MET SAM
AND IT WAS INCREDIBLE BECAUSE IT
WAS THE FIRST TIME I WENT TO THE
UNITED STATES AS WELL.
THE FIRST TIME I WENT OUT OF MY
COUNTRY, ITALY AND SAW OTHER
CHILDREN WITH PROGERIA.
IT WAS AMAZING BECAUSE AND WE
WERE WEARING THE SAME THING OF
COURSE.
OUR GREATEST GOAL WAS JUST TO
HAVE FUN TOGETHER.
>> ONE MOMENT, SAMMY.
WE'LL HAVE TO SHOW THIS BUT JUST
TELL ME WHEN TO MOVE FORWARD.
>> YEAH, IT IS OKAY.
YOU GUYS PLAYED WITH THAT BALL
FOR I DON'T KNOW HOW LONG.
IT WAS BEAUTIFUL TO STAY
TOGETHER BECAUSE AS YOU CAN SEE
THE FUN WITH SAM AND I WERE
STUPID GUYS SOMETIMES OF COURSE
BUT IT WAS BEAUTIFUL BECAUSE
THERE WAS THIS SENSE OF
COMMUNITY AND THE FIRST TIME I
SAW OTHER PEOPLE WITH PROGERIA
WAS THE FIRST TIME FOR MY
PARENTS AS WELL.
NOTHING WAS REALLY KNOWN ABOUT
PROGERIA SO IT WAS BEAUTIFUL TO
MEET EACH OTHER AND EXCHANGE
INFORMATION AND ADVICES AND FOR
US, LITTLE CHILDREN, WE SAW
THERE WERE OTHER PEOPLE LIKE US.
IT WAS VERY AMAZING.
YOU CAN SEE HERE IN THIS
COMMUNITY FEELING HERE IS LESLIE
AND SCOTT WERE IN FLORENCE IN
ITALY WITH MY PARENTS AND I.
THEY CAME FOR VACATION AND WE
MET TOGETHER AND IT WAS AMAZING
BECAUSE THIS IS EXACTLY WHAT THE
PROGERIA COMMUNITY IS ABOUT.
IT'S NOT JUST TO STAY TOGETHER
BECAUSE WE NEED IT BUT TO STAY
TOGETHER BECAUSE WE WANT IT.
WITH LESLIE AND SCOTT AND SAM OF
COURSE, A GREAT FRIENDSHIP WERE
BORN AND WE HAD SO IN OCCASION
TO COLLABORATE AND THE NEED TO
SPEND QUALITY TIME TOGETHER AND
WE WERE IN ITALY SO IF WE DRINK
BEFORE 21 YEARS OLD IT WAS
BECAUSE IT IS LEGAL.
OKAY, VERY BAD JOKE.
SO FRIENDSHIP IS ABSOLUTELY
IMPORTANT FOR EVERY ONE WITH
PROGERIA.
SO IT WAS BEAUTIFUL TO MEET
TOGETHER WITH OTHER PEOPLE AND
CHILDREN WITH PROGERIA.
IT'S BEAUTIFUL FOR THE PATIENTS
THROUGHOUT THEIR OWN COMMUNITY
AT HOME SO HERE FOR EXAMPLE YOU
CAN SEE MY FRIENDS AND I HAVING
FUN.
I HAD THE OPPORTUNITY TO RUN AND
IT WAS AMAZING.
IT WAS A BEAUTIFUL TRIP AND HERE
YOU CAN SEE MY FRIEND AND A RUN
THE MARATHON TOGETHER BECAUSE TO
RUN AND WALK IS SOMETHING I
CAN'T DO.
I CAN'T WALK FOR SO LONG OR RUN
AT ALL.
TO RUN IS THE THING YOU CAN'T
DO, WE WILL DO IT.
AND FRIENDS ARE BEAUTIFUL FOR
ME.
THEY'RE ONE OF THE REASONS I
WAKE UP EVERY MORNING WITH A
SMILE THEY ARE LIKE A FAMILY FOR
ME AND I COULDN'T STAY WITHOUT
THEM.
SO AS LESLIE WAS TELLING BEFORE,
THE NONPROFITS ARE EXTREMELY
IMPORTANT FOR ANY RARE DISEASE.
AS A FAMILY, WE WERE VERY LUCKY
BECAUSE WHEN MY PARENTS AND I
WENT FOR THE FIRST TIME FOR
MEETING THE OTHER KIDS THE
PROGERIA FOUNDATION WAS FUNDED
ONE YEAR BEFORE SO WE HAD
SOMEONE WORKING FOR US, SOMEONE
WORKING FOR MY LIFE, FOR GIVING
ME A BETTER QUALITY OF LIFE AND
BETTER LIFE EXPECTANCY.
IT WAS GREAT TO KNOW THIS
BECAUSE WE WERE NOT ALONE.
WHEN I WAS 10 YEARS OLD I
DECIDED IT WAS TIME FOR ME AND
FOR US AS A FAMILY TO DO
SOMETHING AND ASKING MY PARENTS
WHY IN THE TELEVISION PEOPLE ARE
TALKING ABOUT SO MANY DIFFERENT
DISEASES BUT NOT ABOUT PROGERIA
AND THEY TOLD ME PROGERIA IS TOO
RARE.
WE SHOULD FOUND A FOUNDATION FOR
PROGERIA AND I TOLD THEM, OKAY,
LET'S DO THAT AND WE DID IT.
IT WAS A GREAT CHANGE IN MY
LIFE.
MY PRIVATE LIFE IS ALMOST GONE
NOW BECAUSE MY FOUNDATION IS
VERY ACTIVE.
WE'RE DOING SO MANY DISCLOSURE
EVENTS AND IMPORTANT THE
COLLABORATION WITH THE PROGERIA
FOUNDATION BECAUSE IT HAD A
STRUCTURE WE DIDN'T NEED TO
INVENT ANYTHING JUST SAY TO
OURSELVES, OKAY, IT'S TIME TO DO
WHAT THEY ARE DOING.
--
>> I'M CURIOUS, WHAT ARE YOU
DOING RIGHT IN THE LOWER RIGHT
OF THIS PICTURE AND THERE'S A
MASSIVE NUMBER OF PEOPLE AND
YOU'RE STANDING ON THE STAGE
TAKING A SELFIE WITH YOU AND
THEM IN THE BACKGROUND.
WHAT IS GOING ON?
>> I WAS IN PADUA AND THERE WERE
LIKE 100,000 YOUNG PEOPLE THERE.
IT WAS CRAZY.
IT WAS FOR SUSTAINING PEACE IN
GENERAL AND ASKED ME TO TALK
ABOUT MY LIFE AND ABOUT RESEARCH
BECAUSE RESEARCH IS IMPORTANT
FOR PEACE TOO BECAUSE IT'S
INTERNATIONAL AND A BEAUTIFUL
PLATFORM TO MAKE ALL THE PEOPLE
THE SAME, NO DIFFERENCES OR AT
LEAST WITH DIFFERENCES BUT
COLLABORATING ONE ANOTHER AND IT
WAS ABSOLUTELY CRAZY BECAUSE TO
SEE ALL THOSE PEOPLE IN FRONT OF
ME WAS SCARY AND FUNNY AT THE
SAME TIME.
IT WAS AMAZING.
THE BEAUTIFUL THING IS THAT I
CAN SEE SO MANY PEOPLE
INTERESTED IN WHAT WE'RE DOING.
THERE'S A HUNGER FOR RESEARCH.
THEY WANT TO KNOW WHAT WE ARE
DOING AND IT IS GREAT BECAUSE
THE OVERWHELMING MAJORITY OF THE
PEOPLE DON'T KNOW ABOUT PROGERIA
OR HAVE NEVER SEEN A PERSON WITH
PROGERIA BUT THEY ARE INTERESTED
IN SUSTAINING US AND THAT'S
GREAT.
THIS IS MY BEST PORTRAIT.
I WAS IN ROSWELL AND IT WAS
FUNNY BECAUSE THEY'RE KNOWN FOR
THE CRASH IN 1947.
USUALLY BABIES TELL ME YOU LOOK
LIKE AN ALIEN.
SO I GOT MY REVENGE ON THE
WORLD.
I PLAYED THE ALIEN PART IN
ROSWELL AND IT WAS AMAZING TO
SEE THE FACES OF THIS PEOPLE
THERE LOOKING AT ME AND SAYING,
WHAT IS GOING ON.
IT'S REAL.
I REALLY EXIST.
SO YEAH, I'M DEFINITELY A STUPID
GUY.
IT WAS BEAUTIFUL TO JOKE INSIDE
THE MUSEUM.
SO IF PROGER YA DOES NOT AVOID
ANYONE TO HAVE A HAPPY LIFE AND
TO ENJOY LIFE, PROGERIA IS A
DISEASE SO IT'S SOMETHING WE
HAVE TO FIGHT.
AND TO LIVE WITH PROGERIA IS NOT
SIMPLE.
THERE'S NOT ONLY A RARE DISEASE
IT'S A VERY CRITICAL AND
DIFFICULT DISEASE TO WORK WITH.
PROGERIA IS SOMETIMES PAINFUL.
YOU HAVE PROBLEMS IN THE BONES
YOU HAVE PAIN EVERYWHERE YOU
HAVE PAIN IN THE FOOT, YOU CAN'T
WALK A LOT AND DISLOCATIONS OF
THE HIPS SO YOU HAVE TO STAY IN
THE BED FOR A LONG TIME UNTIL
YOU GET BETTER AND IT IS VERY
DIFFICULT BECAUSE IT IS PAINFUL.
IT'S NOT EASY TO MANAGE.
IN ANY CASE, PROGERIA BECAUSE OF
ALL THESE PROBLEMS AVOID YOU TO
BE AUTONOMOUS OR INDEPENDENT AT
WHATEVER PERCENT.
IN ANY CASE TOGETHER WITH THE
PAIN THERE'S THE CONSCIOUSNESS
YOU'RE IN THE WORLD NOT BUILT
FOR YOU BECAUSE EVERYTHING --
HERE YOU CAN SEE WHEN I HAD MY
SURGERY, IT WAS A DIFFICULT
MOMENT IN MY LIFE.
THE RISK WAS HIGH, 50/50.
50% IT WAS OKAY, 50% I WASN'T
ABLE TO SURVIVE.
IT WAS VERY DIFFICULT TO MAKE A
CHOICE BUT I HAD NO OTHER OPTION
HAVE THE SURGERY OR WAIT UNTIL
IT WAS TOO LATE.
THIS IS WHAT PROGERIA IS.
TOO MANY TIMES I HAD TO SAY
GOOD-BYE TO OTHER PATIENTS AND
IT IS NOT JUST TO SAY GOOD-BYE
TO A PATIENT.
IT IS ABOUT TO SAY GOOD-BYE TO A
FRIEND.
AND IT IS VERY VERY DIFFICULT
BECAUSE THEY ARE FRIENDS AND
SURELY YOU SAY IT COULD BE ME.
WHY AM I HERE AND THEY ARE NOT.
THIS IS WHAT PROGERIA IS ABOUT.
PROGERIA LED ME TO DISCUSS
SCIENCE IS MY FRIEND AND IT WAS
A VERY SCIENTIFIC END AND I
DECIDED TO BE A SCIENTIST FOR
STUDYING PROGERIA BUT I DECIDED
TO BE A SCIENTIST BECAUSE I SAW
THE DRAW IN SCIENCE SINCE I WAS
VERY YOUNG.
I WAS LOOKING AT LESLIE AND HER
TEAM WORKING VERY VERY HARD FOR
HELPING ME AND I THOUGHT OKAY, I
WANT TO BE THAT KIND OF PERSON
BECAUSE I WANT TO HELP PEOPLE
AND MAYBE THERE'S NOT ANOTHER
WAY FOR ME TO BE HELPFUL TO
PEOPLE.
NOW, CAN I SAY WE'RE COLLEAGUES?
>> YES, WE CAN.
>> AND I'M SO PROUD.
>> WE'RE SO PROUD TO BE
COLLEAGUES OF YOURS TOO.
THANK YOU, SAMMY.
I THINK WE HAVE TIME FOR ONE
QUESTION FROM THE WEB.
IS THERE SOMEBODY THAT TYPED IN
A QUESTION WE MIGHT WANT TO
ANSWER?
I'D LIKE TO ASK SOMETHING.
SAMMY, WHEN I FIRST MEET
FAMILIES WHEN THEY'RE NEWLY
DIAGNOSED OR COME TO ME WITH
DIAGNOSTICS, ABOUT WHAT ADVISE
TO YOU GIVE THE FIRST TIME?
>> THIS IS A VERY GOOD QUESTION.
IT'S DIFFICULT TO GIVE SOMEONE
ADVICE BECAUSE EVERYONE IS
DIFFERENT.
EVERYONE TAKES IT IN DIFFERENT
WAY.
CERTAINLY THE FIRST THING WE SAY
NOW IS OKAY.
THERE IS AN INTERNATIONAL TEAM
WORKING FOR YOUR SOUL OR FOR
YOU.
IT'S DIFFICULT.
NOBODY IS HIDING IT BUT THERE IS
A HOPE THERE'S A POSSIBILITY TO
STAY BETTER.
THERE'S A POSSIBILITY TO MANAGE
PROGERIA BETTER THAN IN THE
PAST.
THIS IS THE FIRST THING WE SAY
AND THE OTHER THING IS YOUR SON,
YOUR DAUGHTER, HAS A DISEASE,
OKAY.
BUT FIRSTLY, THEY ARE A PERSON
AND HE OR SHE HAS TO DEVELOP AS
NORMAL AS POSSIBLE AND HE CAN DO
A LOT IN HIS LIFE SO PROGERIA
DOES NOT AVOID TO BE -- TO BE A
PERSON -- TO BE REAL AND
AUTHENTIC.
THIS IS THE FIRST THING.
I HAVE A QUESTION FOR YOU TOO,
LESLIE.
SOMETIMES EMOTION AND HUMOR --
THE HUMAN PART OF A PERSON IS
SEEN AS OPPOSITION TO THE
SCIENTIFIC PART BECAUSE OF THE
NATIONALITY AND WHO COULD
EXPLAIN BETTER THIS THING
>> I'LL KEEP IT SHORT BECAUSE WE
WANT TO GET TO FRANCIS' EXCITING
NEXT PART AND SAMMY, YOU ASKED A
PERFECT QUESTION BECAUSE IT'S
THE LOVE AND THE PASSION THAT
DRIVES YOU TO DO THE BEST
SCIENCE POSSIBLE AND I THINK
IT'S BORN OUT WHEN YOU DO YOUR
SCIENCE, IT REALLY MEANS
SOMETHING.
IT'S GOING TO BE TRANSLATED INTO
SOMETHING.
YOU HAVE A HYPOTHESIS AND THAT
TURNS OUT TO BE WRONG, YOU WANT
TO KNOW.
YOU WANT TO SAY, OKAY, THIS WAS
WRONG, LET'S MOVE ON BECAUSE I
DON'T WANT TO GO DOWN THE WRONG
PATHWAY.
YOU WANT TO GO DOWN THE RIGHT
PATHWAY SO YOU JUST PICK
YOURSELF UP AND START AGAIN AND
START SOMETHING NEW.
SO THE PASSION IS THERE FOR
FAMILY MEMBERS LIKE ME AND
SCIENTISTS AND CLINICIANS AND
THERE ARE FOR US ALL.
IT'S THE BEST PART AND NOT A
DISADVANTAGE.
THAT'S A PERFECT TRANSITION TO
OUR PASSIONATE SCIENTISTS.
FRANCIS, CAN YOU TELL US ABOUT
YOUR JOURNEY?
>> WE'LL HEAR MORE FROM SAMMY
AND TO BE PART OF THIS WITH
LESLIE MY FRIEND NOW OVER 20
YEARS AS WE TOGETHER TRY TO
FIGURE OUT WHAT TO DO ABOUT THIS
TERRIBLY RARE BUT POIGNANT
DISORDER CALLING OUT FOR
SOMEBODY TO FIGURE IT OUT.
I FIRST MET LESLIE AND SON SAM
23 YEARS AGO.
THIS WAS SHORTLY AFTER THEY
STARTED PROGERIA SEARCH
FOUNDATION AND HOW DO WE GET
SOMEBODY TO WORK ON ?
WE HAD A GOOD TIME WORKING ON
THIS AND LESLIE AND SCOTT WERE
COMPELLING PEOPLE.
I SAID, SURE, I'LL TRY TO HELP A
LITTLE BIT AND TRY TO IDENTIFIED
SCIENTISTS WHO MAY WANT TO
POTENTIALLY WORK ON THIS RARE
DISEASE.
MAYBE I CAN HELP SET UP AN IDEA
FOR A WORKSHOP AND I GOT HOOKED.
IT WAS A POSTDOC IN MY LAB WHO
DECIDED SHE WAS GOING TO TRY TO
FIND THE GENE BECAUSE IT JUST
SEEMED LIKE SOMETHING THAT
NEEDED TO HAPPEN.
MEANWHILE ALONG THE WAY I GOT TO
SPEND TIME WITH LESLIE AND SCOTT
AND SAM AND PLAYING MUSIC WITH A
GOOD DRUMMER, SAM WAS.
AND THEN ON DOWN THROUGH THE
YEARS I WOULD SAY SAM AND I
BECAME REALLY GOOD FRIENDS.
HERE'S A MUCH LATER PICTURE IN
THE CIRCUMSTANCE OF A
PRESENTATION THAT INVOLVED
COOKIE MONSTER AND OF COURSE
NEEDED A PICTURE WITH COOKIE
MONSTER.
WE LOST SAM AT AGE 17.
HE'S AN OUR HEART EVERY TIME WE
TALK ABOUT THIS DISEASE AND WORK
ON THIS DISEASE.
I'M GLAD TO HAVE HIS FRIEND
SAMMY, HERE AS AN AMAZING
CONTRIBUTOR.
AND I GOT A CALL SAYING I THINK
WE HAVE SOMETHING IT LOOKS LIKE
THE DNA SAMPLES WITH PROGERIA
SEEM TO SHARE AN UNUSUAL
SPELLING IN THE LAMIN A GENE AND
LOOKS LIKE A SILENT MUTATION AND
HOW CAN THAT BE POSSIBLY THE
RIGHT ANSWER.
AS YOU CAN SEE, WE PUBLISHED A
PAPER AND FIGURED OUT IT WAS THE
RIGHT ANSWER AND THESE WERE
RECURRENT DE NOVO POINT
MUTATION.
THE WAY WE FIGURED OUT WAS THIS
HAD TO BE THE CAUSE WE HAD
SEVERAL PARENTS WHOSE KIDS WERE
AVAILABLE AND A C2 MUTATION IN
THE LAMIN A GENE AND THE PARENTS
DIDN'T HAVE IT AND A MUTATION IN
THE SAME NUCLEOTIDE WHAT IS
GOING ON HERE.
WE LOOKED AT THE SEQUENCE AND
THERE YOU SEE THE C TO A T AND
I'M SURE YOU ALL MEMORIZED THE
GENETIC CODE, MAYBE NOT.
I HAD TO LOOK IT UP AND THERE'S
ANOTHER POINT THE POINT MUTATION
CAUSES TROUBLE FOR THIS
PARTICULAR GENE AND THAT'S
BECAUSE IT ACTUALLY CREATES OR
ACTIVATES, I SHOULD SAY, A
CRYPTIC SPLICE SITE DONOR IN THE
MIDDLE OF AXON 11 USED A LITTLE
BIT BY ALL OF YOU BUT IN A LOW
LEVEL EXCEPT MAKE WHEN YOU'RE
CELLS ARE REALLY HEADING FOR
SENESCENCE IN WHICH IT TURNS ON
A BIT.
IN THESE KIDS THAT ONE LETTER
CHANGE MAKES THE SEQUENCE IN
AXON 11 BETTER TO THE SPLICE
DONOR CONSENSUS.
WE POSTULATED PROBABLY THE SAME
DAY OR AT LEAST THAT WEEKEND
THAT MIGHT BE THE MECHANISM AND
YOU'RE ACTIVATING THEREFORE A
SPLICE THAT BASICALLY SKIPS OVER
THE LAST PART OF AXON 11.
ALL OF YOU MOLECULAR BIOLOGISTS
ASKING IF THAT'S A MULTIPLE WITH
THREE NUCLEOTIDES, YES.
150 NUCLEOTIDES THAT GETS
SKIPPED.
WHAT'S THAT MEAN WHEN YOU MAKE
THE PROTEIN?
YOU'LL MAKE A LAMIN A PROTEIN
MISSING 15 ACIDS AND YOU HAVE
STILL HAVE AXON 12 AND WE CALL
THAT PROGERIA.
THAT PROTEIN.
BOTTOM LINE THIS MAKES THE CELL
SENESCE PREMATURELY BECAUSE IT
REALLY MESSES UP THE NUCLEAR
STRUCTURE.
SO WHY WOULD THAT CAUSE A TOXIC
PROTEIN?
WE NEEDED TO DEPEND ON THE
WONDERFUL BASIC SCIENCE DONE BY
PEOPLE STUDYING LAMIN A AND JUST
STOOD ON THEIR SHOULDERS AND SEE
IMMEDIATELY WHY THIS COULD BE A
PROBLEM NORMALLY LAMIN A HAS
POST TRANSLATIONAL PROCESSING
WHERE IT HAS AS ITS C TERMINUS A
HYDROPHOBIC TAIL AND THERE'S A
CLEAVAGE PROCESS THAT COMES
ALONG AND REMOVES THAT SO MATURE
LAMIN A IN THE LOWER LEFT IS NO
LONGER ANCHORED BY THE
PARTICULAR TAIL.
SO WHAT IS THAT DOING?
WE THINK THE REASON IT'S THERE
IS IT'S KIND OF A ZIP CODE.
THIS PROTEIN NEEDS TO LIVE ON
THE INNER SURFACE OF THE NUCLEAR
SCAFFOLD UNDER THE NUCLEAR
MEMBRANE AND THE TAIL HELPS IT
GETS THERE BUT THEN YOU WANT IT
RELEASED OTHER WISE OTHER
PROTEINS ARE STUCK TOO AND SOON
YOU HAVE DONE A BAD THING TO THE
NUCLEAR STRUCTURE.
WITH THE PROGERIA MUTATION,
THOSE 50 AMINO ACIDS CONTAIN THE
RECOGNITION SITE FOR THE ENZYME
CALLED ZMC24 AND CAN'T BE
RECOGNIZED AND YOU NO CLEAVAGE
AND HAVE A PERMANENT LAMIN A AND
CAUSES HAVOC.
THAT'S A GOOD SUMMARY OF WHAT WE
THINK THE MECHANISM IS.
WHAT YOU SEE, YOU CAN SEE A
COUPLE CELLS ON THE LOWER LEFT
IS NORMAL CELL STAINED WITH
LAMIN A.
IT'S NICE OVAL SHAPE.
ON THE RIGHT IS A PROGERIA CELL
THAT'S GONE THROUGH A FEW
PASSAGES AND NOT A NORMAL
LOOKING NUCLEUS AND IRREGULAR
AND HAS WEBBING BECAUSE THE
STRUCTURE HAS BEEN DISTURBED BY
THESE PROTEINS WHICH IN THE
UPPER DIAGRAM ARE SHOWN AS GREEN
CANDLE STICKS WITH THE OVAL
STUCK IN THE MEMBRANE AND THE
OTHER THINGS HAPPEN AS A RESULT
OF THAT.
YOU GET WEBBING IN THE NUCLEUS
AND CHROM CHROMATIN
DISORGANIZATION AND LAMIN A
PLAYS A ROLE INSIDE THE NUCLEUS
AND OVER ALL YOU GET EARLY
REPLICATED SENESCENCE.
YOU IF TAKE A FIBROBLAST WITH A
PERSON FROM PROGERIA IT WILL
SENESCE LONG BEFORE SOMEBODY WHO
DOESN'T HAVE THIS CONDITION.
QUICKLY, WE HAD A GOOD IDEA OF
THE BIOLOGICAL PROBLEM.
WHAT ARE WE GOING DO ABOUT IT?
WE FIGURED IF WE WANT TO
UNDERSTAND THIS AND MOVE IT IN
THE DIRECTION OF ANY KIND OF
THERAPY, WE NEED AN ANIMAL
MODEL.
WE WANTED AN ANIMAL MODEL AS
CLOSE AS POSSIBLE TO THE HUMAN
CONDITION.
WE COULD HAVE GONE IN AND MUTATE
THE MOUSE LAMINATED GENE AND OUR
MODEL HAS THE HUMAN GENE
INSERTED INTO IT.
IT'S A TRANSGENIC.
BUT WE WANTED THE TRANSGENIC TO
CARRY ALONG WITH IT THE
REGULATORY SIGNALS FOR LAMIN A
AND GET EXPRESSED IN THE RIGHT
TIME OR TISSUE AND BIG PIECE OF
DNA AND RETRO ENGINEERED WITH
G6O8G WHICH IS WHAT WE CALL IT
AND ACTING THE SPLICE DONOR.
THIS MOUSE MODEL WE'VE HAD IN
THE LAB QUITE A LONG TIME GOING
ON 15 YEARS HAS BEEN A SOURCE OF
EXPERIMENTS WE CAN DO TO ASSESS
THE ACTUAL CAUSE AND MOST
IMPORTANTLY WHAT KINDS OF
THERAPIES MIGHT HELP.
YOU CAN SEE WHAT THE MICE LOOK
LIKE BUT YOU WANT TO SEE THE
PHENOTYPE COME ON AS EARLY AS
POSSIBLE.
WE BREED THESE NICE TO
HOMOZYGOUS AND THIS IS IN BAD
SHAPE AND THE MOUSE WILL NOT
LIVE MORE THAN ANOTHER WEEK OR
SO.
COMPARED TO WILD TYPE THEY'RE
SMALL AND BY THE TIME THEY GET
TO FIVE TO SIX MONTHS THEY'RE
CLEARLY SHOWING A LOT OF THE
SIGNS OF PROGERIA AND
IMPORTANTLY THAT INCLUDES THE
CARDIOVASCULAR DISEASE AS I'LL
SHOW IN A MINUTE.
THIS IS A PRETTY DARN GOOD MODEL
OF THE HUMAN DISEASE.
IT DOESN'T ALWAYS WORK THAT WAY
WHEN YOU MAKE A MOUSE THEN YOU
TRY TO CREATE A MUTATION THAT
OUGHT TO BE THE SAME OF THE
HUMAN SOMETIMES NOT SO MUCH BUT
WE HAVE A GOOD OPPORTUNITY TO DO
WORK WITH A MODEL SIMILAR TO THE
HUMAN.
WHAT HAPPENS IN THE
CARDIOVASCULAR SYSTEM.
PROBABLY NOT A LOT OF YOU ARE
USED TO LOOKING AT SECTIONS OF
THE AORTA IN THE MOUSE AND THIS
IS WHERE A LOT OF THE MOST
SEVERE DAMAGE HAPPENS IS IN
LARGE VESSELS AND THE A -- AORTA
IS THE LARGEST VESSEL.
THESE HAVE SIX-MONTH-OLD MICE.
THE COLUMN ON THE RIGHT IS THE
DOUBLE COPY HOMOZYGOUS GENE AND
I DON'T THINK YOU CAN SEE ALL
THE DETAILS BUT YOU CAN SEE THIS
EXTENSIVE THICKENING OF THE
OUTSIDE OF THE VESSEL IN THE
NORMAL THAT'S NOT ALL THERE AND
THIS IS WHAT WAS MENTIONED AND
HERE IT'S VERY THICK AND THAT'S
THE HALLMARK OF THIS IN THE
MOUSE AND HUMAN CONDITION.
IF YOU LOOKED AT A HIGHER LEVEL
RESOLUTION YOU'D ALSO SEE
SOMETHING PROFOUND THAT IS THE
MEDIAL LEVEL LAYER OF THE AORTA
WHICH IS WHERE THE SMOOTH MUSCLE
CELLS ARE ACELLULAR AND IT'S THE
VASCULAR SMOOTH MUSCLE CELLS
WITH THE GREATEST SENSITIVITY TO
PROGERRIN AND THEY DISAPPEAR AND
THIS IS A CELLULAR AND PRONE TO
ATHEROSCLEROSIS OF STROKES IN
HEART ATTACKS IN KIDS ARE THE
SAME THING THAT NOW HAPPEN IN
THE MOUSE.
AGAIN, A GOOD MODEL.
PEOPLE HAVE DONE WORK ON LAMIN A
BIOLOGY SO WE HAD SOMETHING
GOING AND MAYBE WE CAN DIAL BACK
THE AMOUNT OF THE TOXIC PROTEIN
BY BLOCKING THE STEP FOR WHICH
ACTUALLY A KNOWN CLASS OF DRUGS
ALREADY HAD BEEN DEVELOPED.
THOSE ARE TRANSFERASES.
THEY NORMALLY ATTACH AND THERE
ARE TRANSFERASE INHIBITORS BEING
DEVELOPED BECAUSE THE ONCA
PROTEIN AND THEY THOUGHT THEY
COULD CURE CANCER AND FOR
COMPLICATED IT DOES NOT WORK FOR
RAS AND CANCER APPLICATIONS BUT
WE SAID LET'S TRY AND SEE.
WE DON'T EXPECT THIS TO BE A
CURE BECAUSE YOU'RE DIALING BACK
THE AMOUNT OF PROGERIN AND NOT
ELIMINATING IT AND YOU WORRY
ABOUT TOXICITY BECAUSE YOU'RE
AFFECTING ALL PROTEINS IN SOME
WAY AND THE FIRST CELL
EXPERIMENT UP ON THE FIFTH FLOOR
HERE AS A TRAINEE SHOWED
REMARKABLE RESULTS IN THIS SPACE
OF 72 HOURS.
TWO DIFFERENT PROGERIA CELL
LINES SHOWING EITHER ONE OR TWO
MICROMOLAR OF A TRANSFERASE
INHIBITER NUCLEIZED THE SHAPE
AND THIS SHOWS MORE DETAILS
ABOUT THE CELLS.
LOOK FIRST AT THE UPPER ROW.
THE WILD TYPE MICE AND YOU CAN
SEE THE PINK GLOBULES ARE NUCLEI
IN THE VASCULAR SMOOTH MUSCLE
CELLS AND THE GREEN STUFF IS
SMOOTH MUSCLE ALPHA ACTIN THE
PROTEINS THE CELLS DEPEND ON.
THIS IS A HEALTHY LOOKING AORTA.
NOW LOOK AT THE PROGERIA.
LIKE I SAID THE CELLS ARE JUST
GONE.
THERE ARE NO NUCLEI TO SPEAK OF.
YOU CAN SEE IT'S STAINED WITH
PROGERIN THERE'S SOME GHOSTS
LEFT BEHIND WHERE MAYBE THERE
WERE ONCE NUCLEI BUT THEY'RE
GONE AND IT'S A WASTELAND.
YOU SEE THE SQUIGGLY GREEN GUYS.
WHAT HAPPENS IF YOU TREAT THE
MOUSE STARTING AT AN EARLY AGE
WITH A TRANSFERASE INHIBITOR.
CHECK IT OUT.
THIS SHOWS YOU AT THE SAME POINT
AT NINE MONTHS YOU COULD
ESSENTIALLY PRESERVE THE
ARCHITECTURE OF THE AORTA.
NOT QUITE ENTIRELY.
YOU CAN SEE SOME PLACES WHERE
YOU DON'T HAVE AS MANY NUCLEIS
AS YOU SHOULD BUT IT'S LOOKING
LIKE A GOOD IDEA.
OKAY, WE'RE ON THE RIGHT PATH
BUT WE'RE A BASIC SCIENCE LAB.
WE DO GOOD CELL BIOLOGY AND
MOLECULAR GENETICS AND WHAT WE
WANT TO DO IS WILL THIS BENEFIT
A PATIENT.
THAT'S WHERE I HAVE TO TALK TO
MY FRIEND LESLIE AND SAY, OKAY,
IS IT POSSIBLE WE MIGHT ACTUALLY
MOUNT A CLINICAL TRIAL WITH THIS
CLASS OF DRUGS?
HOW IN THE WORLD YOU WOULD DO
THAT WITH SUCH A RARE DISEASE
WITH KIDS ALL OVER THE WORLD?
HOW WOULD YOU DO THAT?
>> BEFORE WE GET TO THAT I'D
LIKE TO ASK YOU A QUESTION.
HOW DID YOU FEEL -- YOU
DISCOVERED THE GENE -- I GUESS
OUR TEAM, BUT YOU LED THIS
DISCOVERY.
YOU HADN'T EVEN FINISHED THE
HUMAN GENOME PROJECT AND WERE
75% OR SO THROUGH.
HOW DID YOU FEEL AND WHAT WERE
YOUR HOPES?
WHAT DID YOU THINK?
FRANCIS: THIS WAS AN AMAZING
COMPELLING OPPORTUNITY AS A
SCIENTIST TO DO INTERESTING
DETECTIVE WORK TO SORT OUT THE
CAUSE OF THE DISEASE.
RECOGNIZE THIS WAS A HARD ONE TO
FIGURE OUT BECAUSE IT DOESN'T
RUN IN FAMILIES SO THE THINGS
GENETICISTS DO WASN'T AVAILABLE
AND FINDING THE STRAIN WAS AN
ARTICLE IT WAS ACADEMICALLY AND
INTELLECTUALLY CHALLENGING BUT
ABOUT TRYING TO FIND KIDS LIKE
SAM AND CASEY WHEN I WAS A
FELLOW IN 1983 WITH THE SAME
DIAGNOSIS AND I FELT POWERLESS
BECAUSE I DIDN'T KNOW ANYTHING
ABOUT IT OR WHAT TO DO TO HELP.
AS A PHYSICIAN SCIENTIST YOU
DREAM OF A DAY WHERE YOU HAVE A
COMBINATION OF SOMETHING
SCIENTIFICALLY CHALLENGING AND
THIS WAS A PARTICULAR COMPELLING
ONE.
THANK YOU.
THAT WAS GREAT TO HEAR.
THIS IS WHERE THE HUMAN BRIDGE
COMES IN.
TODAY THERE ARE 16 KIDS IN THE
U.S.
WE HAD BEEN BUILDING THIS
REGISTRY AND KEEPING IN TOUCH
WITH FAMILIES AND BUILDING A
FAMILY HISTORY OF CLINICAL
CHARTS.
WE WERE GOING TO MAKE A LEAP.
I DON'T REMEMBER DOUBTING WE'D
DO THIS SO THAT'S WHAT WE DID.
WE STARTED FIRST HERE AT THE
CLINICAL CENTER WITH A NATURAL
HISTORY STUDY THAT GRADUATES YOU
FROM CLINICAL CHARTS TO SEEING A
SERIES OF EIGHT OR NINE KIDS A
SERIES OF INVESTIGATING THE
NATURAL HISTORY BECAUSE NOBODY
KNEW WHAT IT WAS FROM AN
OBJECTIVE PERSPECTIVE AND
OUTCOME MEASURES AND OBJECTIVE
MEASURES OF SUCCESS WOULDN'T BE
POSSIBLE WAY BACK THEN WITHOUT
SUCCESS AND THEN WE FOUND THE
WORLD'S LEADER IN LONFARNIB AND
I HAD AN AMAZING COLLEAGUE I
HAVE TO CALL OUT BECAUSE SHE HAD
BEEN INVOLVED WITH AND LEAD WITH
EARLY DAYS.
THESE CLINICAL TRIALS ALL SEEN
HERE.
WE LAUNCHED THE FIRST CLINICAL
TRIAL FOR PROGERIA AND BOSTON
CHILDREN'S HOSPITAL WHILE
BUILDING THIS TEAM OF EXPERTS
THEY WERE NOW THE WORLD'S
EXPERTS BECAUSE NOBODY WAS THE
WORLD'S EXPERT AND THEY REMAINED
SO.
AND WE WANT TO GET THE WORD OUT.
SO WE HAD A SERIES AND IF YOU'LL
NOTE IN ALL THE CLINICAL TRIALS,
LONAFARNIB IS THE COMMON
DENOMINATOR AND KEPT IT ON BOARD
FROM 2007 TO NOW AND THAT WILL
BE IMPORTANT TO WHAT I TELL YOU
NEXT.
WE BROUGHT THE CHILDREN IN
PAIRS.
WE STILL DO AND THEIR FAMILIES
BECAUSE A WEEK OF TEST IING AN
COUNTRY WHERE YOU DON'T SPEAK
THE LANGUAGE IS DIFFICULT TO THE
KIDS AND FAMILIES SUPPORT EACH
OTHER.
MAYBE SAMMY WILL TALK ABOUT THAT
AFTER I FINISH THIS SESSION.
AFTER TWO YEARS OF TREATMENT WE
HAD EVIDENCE.
WE WERE WORKING OUT THE HISTORY
AND THE VASCULAR STIFFNESS
WASN'T KNOWN AND WE FOUND AN
INCREASE AND MOST IMPORTANTLY,
CARDIOVASCULAR STIFFNESS AND
I'LL SHOW A COUPLE SLIDES WAS
IMPROVED.
BONE STRUCTURE NOT THE DENSITY
BECAUSE THE DENSITY'S PRETTY
OKAY BUT THE BONE STRUCTURE GOT
MORE TOLERANT TO BENDING AND
TWISTING AND SOME HEARING
IMPROVEMENTS.
OTHER THINGS WERE NOT AFFECTED.
WE DIDN'T IMPROVE THE THAT'S
WHAT WE WERE GOING FOR WITH THE
CURE.
THE CARDIOVASCULAR MEASURE OF
THE INTEGRITY OF THE STIFFNESS
OR FLEXIBILITY OF YOUR BLOOD
VESSELS WAS IMPROVED AND THIS
WAS A DISCOVERY LED AT THE
BRIGHAM AND WOMEN'S SO PULSE
WAVE VELOCITY MEASURES
STIFFNESS.
A HIGHER NUMBER IS NOT GOOD.
A LOWER NUMBER SAY BETTER NUMBER
AND ALL BUT ONE OF THE KIDS
DECREASED BY A LOT OF.
AND THE DECREASE THEY
EXPERIENCED WAS -- IF YOU
DECREASE ONE METER PER SECOND IN
THE ADULT POPULATION THE CHANCE
DECREASE AND THIS IS 3 1/2.
I REMEMBER THE DAY WE FOUND
THIS.
I WAS LIKE DID IT REALLY WORK?
THIS WAS THE FUNCTIONAL MEASURE
OF VASCULAR PATHOLOGY AND THIS
IS THE ACTUAL ULTRASOUND AND
WHAT YOU'RE SEEING IS THE WALL
OF THE VESSEL, THE OF THE ARTERY
FRANCIS WAS SHOWING YOU FROM THE
MICE AND BROUGHT IS BAD.
BRIGHT SHOWS YOU LESS CELLS,
MORE COLLAGEN, MORE OF THOSE
TYPES OF STIFF THINGS SO THIS IS
SOMEBODY NORMAL AND THIS IS
SOMEBODY WITH PROGERIA AND A
CHILD WITH PROGERIA AFTER
TREATMENT.
OBVIOUSLY A LOT CLOSER TO NORMAL
THAN AT THE START.
THAT WAS REALLY EXCITING.
IT WASN'T ENOUGH FOR APPROVAL
AND SO WE MOVED ON AND WHAT WE
DID NEXT WAS LATE INCENTIVE.
WE MENTIONED TO THE FDA WE WERE
TRYING TO LOOK AT LIFE SPAN AND
THEY WERE EXCITED BY IT SO WE
LOOKED AND LIFE SPAN DEATH WAS
NOT A PART OF THE CLINICAL
TRIALS OUTCOMES.
WE TOOK INFORMATION OVER THE
YEARS OF BUILDING OUR REGISTRY,
WE TOOK ALL OF THAT INFORMATION
AND CREATED AN EXTERNAL BUT WELL
DEVISED CONTROL GROUP AND CAN
CON -- COMPARE IT TO THE TRIAL
KIDS AND ASK THE BENEFIT AND
EVERY TIME YOU DRAW A CHILD
PASSES AWAY.
THIS IS THE REGISTRY AND THE
CHILDREN WHO DIDN'T GET IT AND
THOSE THAT DID.
ONE DEATH VERSUS NINE.
THIS IS DATA THAT CAME LATER
THAT LONAFARNIB IS EXTENDING
LIFE SPAN BY AN AVERAGE OF 4.3
YEARS FOR A 14-YEAR-OLD AVERAGE
IS A LOT OF BUT CERTAINLY NOT
FLUFF.
-- NOT ENOUGH.
SO WE WERE FORTUNATE ENOUGH TO
BE GETTING DRUG FROM AND
COLLABORATING ON AN AGREEMENT
AND GOT APPROVAL IN 2020 IN THE
U.S. AND 2022 IN EUROPE AND LAST
WEEK IN JAPAN.
WE HAVE TO CHANGE THE NUMBER OF
APPROVED DRUGS.
SAMMY, TELL US MORE.
YOU WERE IN THE TRIAL FROM THE
BEFORE HE BEGINNING.
TELL US ABOUT YOUR TRIAL
EXPERIENCE.
IT WAS CRAZY.
WHEN I STARTED THE MEDICATION
HERE ON THE LEFT I WAS JUST 12
YEARS OLD.
SO I WAS A TEENAGER AND I WAS
CHANGING I UNDERSTOOD I NEEDED
HELP.
I UNDERSTOOD WHAT LIFE
EXPECTANCY WAS IN REAL MATERIALS
AND WAS VERY ANGRY.
IT WAS UNFAIR AND I WAS ANGRY
WITH GOD TOO AND AN THAT MOMENT
ANGRY WITH GOD AS WELL.
PARADOXICALLY I WAS THINKING
THEN TO TAKE SOMETHING TO BE
BETTER GOES AGAINST GOD AND I
WAS A TEENAGER AND I WAS
CONFUSED AND IT WAS MESSY FOR ME
I REPUBLIC I DIDN'T WANT TO DO
IT AND I REMEMBER WITH MY
PARENTS AND I LOVE MY PARENTS.
THEY WANT ONLY THE BEST FOR ME.
THEN I LOOKED AT LESLIE AND SHE
WAS LOOKING AT ME WITH THE SAME
LOOK MY PARENTS WERE LOOKING TO
ME.
BECAUSE FOR LESLIE WE ARE SONS
AND DAUGHTERS AND IF SHE THINK
THIS IS A GOOD THING, I BELIEVE
IN HER.
I BELIEVE IN YOU AND THE SCIENCE
AND A STARTED TO TAKE IT AND I
STARTED TO GROW INTERNALLY.
I UNDERSTOOD WHAT SCIENCE WAS
A
AND UNDERSTAND SCIENCE WAS A
GIFT FROM GOD AND AT THAT MOMENT
I STARTED TO SO UNDERSTAND AND I
WOULDN'T BE MORE GRATEFUL FOR
THAT MOMENT I STARTED.
>> SAMMY YOU'VE GONE ON TO DO
OTHER THINGS AND YOU'RE ABLE
AMBASSADOR OR SOMETHING LIKE
THAT.
BY THE WAY, SAMMY, HOW OLD ARE
YOU?
>> I'M 28 NOW.
IT IS BEAUTIFUL BECAUSE I TELL A
PATIENT THERE'S A DRUG.
IT IS GREAT AND I WAS AMAZED
WHEN YOU WERE TALKING, YOU,
FRANCIS AND LESLIE HOW IT
DEVELOPS AT THE BEGINNING.
IT WAS CRAZY BECAUSE IN SEVEN
YEARS YOU WERE ABLE TO FIND THE
MUTATION CREATE A MODEL AND FIND
THE DRUG AND DRIVE IT INTO THE
CLINICAL TRIAL.
IT WAS AMAZING.
IT'S BEAUTIFUL FOR ME TO EXPLAIN
THIS TO THE OTHERS TO SAY AND
THIS IS MY EXPERIENCE, I'M 28.
THE DRUG IS WORKING.
WE HAVE TO DO MORE.
>> THAT'S THE PERFECT SET UP FOR
ME TO TELL YOU LIKE YOU SAID
THIS IS A TREATMENT NOT A CURE
AND AN ALWAYS TELL FAMILIES THE
NUMBER ONE THING THAT THE
CLINICAL TRIALS SHOWED US IS WE
DISCOVERED SOMETHING WE NEVER
KNEW.
WE CAN REVERSE SOME OF THIS
DISEASE.
IT CAN BE DONE.
EVERYBODY BENEFITTED THE YOUNG
AND OLDER KIDS DID, EVERYBODY.
IT'S SOMETHING WE CAN REVERSE
AND BETTER TREATMENT AND CURE.
FRANCIS: WHERE ARE WE NOW?
IT'S A TREATMENT NOT A CURE.
WE WERE ABLE TO BRING PEOPLE
LIKE SAMMY INTO THEIR 20s WHICH
WAS UNHEARD OF BEFORE AND TO
STOP NOW WOULD MAKE NO SENSE
WHEN WE'RE GETTING OPPORTUNITIES
COMING FROM NEW IDEAS IN SCIENCE
THAT CAN BE INVESTED IN.
I WANT TO TELL YOU ABOUT SOME OF
THE THINGS HAPPENING NOW WHICH
IS VERY MUCH WORK IN PROGRESS.
WHICH WE ARE BOLD ENOUGH TO SAY
MAY TAKE US TO THE NEXT LEVEL OF
INTERVENTIONS WITH THIS
CONDITION MAYBE EVEN THAT CURE
THAT WE ARE ALL DREAMING OF.
AND THREE CATEGORIES.
SMALL MOLECULE DRUGS THE
TRANSFERASE INHIBITOR AND MTOR
INHIBITORS BEING TESTED IN
CLINICAL TRIAL IN BOSTON FOR THE
RESULTS ARE NOT YET CLEAR AND I
WANT TO TALK ABOUT RNA AND DNA
THERAPY BECAUSE AFTER ALL WE'RE
TALKING ABOUT A DISEASE WHERE WE
KNOW WE KNOW THE NUCLEIC ACID
INVOLVED.
THE C TO A T.
DOESN'T SOUND LIKE THAT
SOMETHING YOU'D GO RIGHT TO
WHERE THE ACTION IS TO GET THE
BENEFIT AND THE RNA OR MAYBE THE
DNA.
WE LOOKED AT CELL CULTURE TO BE
ABLE TO BLOCK THAT ABNORMAL
SPLICE THAT CAUSES ALL THE
TROUBLE.
A PMO WAS DESIGN IDEALLY SO IT
WOULD SIT ON TOP OF THE MUTATION
PREVENTING THE SPLICE APPARATUS
FROM RECOGNIZING IT AS A SPLICE
DONOR SO SPLICING WOULD PROCEED
THE WAY IT WAS SUPPOSED TO.
HOW'S THE DATA LOOK?
YOU CAN SEE WHAT WAS SYNTHESIZED
STEPPING ACROSS THE X IN THE
MIDDLE AND DOWN BELOW YOU SEE
THE DATA IN CULTURED CELLS WHAT
HAPPENS WHEN YOU APPLY THESE
PARTICULAR ONE TO THE PRODUCTION
OF LAMIN A PROGERIN THE P OR
LAMBIN C THE DIFFERENT ISOFORM
OF THE SAME GENE THAT STOPS
UPSTREAM OF THE MUTATION SO IT'S
NOT AFFECTED IN PROGERIA AND YOU
CAN SEE THE HISTO GRAMS SHOWING
THE RNA RESULTS BELOW AND THE
WESTERN BLOT.
WE HADN'T SHOWN YOU BEFORE.
YOU CAN SEE PROGERIN ON A
WESTERN BLOT THE MIDDLE BAND AND
THIS GIVES A STRONG RESPONSE IN
TERMS OF KNOCKING WAY BACK ON
PROGERIN AND KNOCKS DOWN LAMIN A
SIGNIFICANTLY.
WE DON'T THINK THAT'S PROBABLY
DANGEROUS.
LAMIN C COMPENSATES BY GOING UP
A BIT.
IF YOU HAD TO PICK ONE, I THINK
YOU PICK ONE AND THAT'S CALLED
SRP2001 AND WORKED WITH A
COMPANY AT THE TIME HENCE THE
SRP.
AND THERE'S A TWICE INTRAVENOUS
INFUSION AND SEEING WHAT WOULD
HAPPEN STARTING EARLY AND
PROGRESSING DURING THE LIFE SPAN
AND YOU CAN SEE IT'S PRETTY
IMPRESSIVE.
WE GOT CLEARLY A SIGNIFICANT
EXTENSION OF LIFE AND JUST THE
APPEARANCE OF THE ANIMAL IS
BETTER.
WE COULD NEVER HAVE DONE THIS
WITHOUT THE SUPERB MOUSE
RESOURCE WE HAVE AT NIH.
I PARTICULARLY GOT A CALL OUT
OUR LONG-TERM MOUSE EXPERT WHO
MAKES ALL THESE THINGS POSSIBLE
WITH VERY LARGE NUMBERS OF
ANIMALS AND RIGOROUS RECORD
KEEPING AND THE ABILITY TO DO
TWICE WEEKLY INTRAVENOUS
INFUSION OF THE SAME MOUSE FOR
MANY WEEKS ON END AND NOT HAVE
THAT BE A PROBLEM.
WE'RE FORTUNATE IN THAT REGARD.
THE HUMAN TRIAL IS THE
CONVERSATION WE SPENT SOME OF
OUR TIME THIS AFTERNOON TALKING
ABOUT.
HOW DO YOU TAKE THIS FINDING TO
A CLINICAL TRIAL.
THIS IS A PEPTIDE OLIGOMER AND
THINK OF IT OF AN RNA BUT HAS A
PEPTIDE ATTACHED MAKING IT MORE
LIKELY TO GET INTO THE CELLS YOU
WANT AND A NAKED ONE WOULD
MORPHOLINNO BECAUSE AWAY WANT
THEM IN THE MUSCLE CELLS AND
THAT WAS HAPPENING.
WHAT TO DO?
IT HAS TO SHIFT OVER TO A MEANS
OF ADMINISTRATION THAT COULD BE
PRACTICAL AND THAT MEANS SUB
CUTANE
CUTANEOUS.
THIS HAS BEEN DONE.
LESLIE AND HER TEAM MANAGED TO
DO THE FORMULATION AND DONE THE
APPROPRIATE CHECKING TO MAKE
SURE IT GETS IN THE SYSTEM IN
THE RIGHT WAY.
NOW IT BECOMES MORE PRACTICAL TO
IMAGINE ADMINISTERING THIS NOT
IN OUT OF THE WAY PLACES THAT
PHARMACO DYNAMICS HAS ALSO BEEN
DONE.
AGAIN, WE'RE TALKING ABOUT
TAKING SOME OF THE FDA.
I WANTED TO BE PART OF THE
DEMYSTIFYING MEDICINE TO BE MORE
EXPLICIT THAN WE SOMETIMES DO
ABOUT HOW TO GO FROM AN ANIMAL
MODEL RESULT TO A CLINICAL
TRIAL.
HAVE YOU A LOT OF THINGS THAT
HAVE TO BE DONE IN A RIGOROUS
WAY OR THE FDA WILL SAY NOT YET,
GO BACK AND START OVER AND IT
COSTS A LOT OF MONEY AND TIME
AND YOU WANT TO DO IT EXACTLY
RIGHT.
THERE NEEDS TO BE ANIMAL STUDIES
TO ASSESS TOXICITY.
THERE'S ALREADY BEEN SOME OF
THAT ON OTHER PPMOs SOME OF
WHICH HAVE GONE TO CLINICAL
TRIALS.
YOU HAVE TO FIGURE OUT WHAT'S
THE RIGHT DOSE AND WHAT'S THE
TOP DOSE YOU COULD GO TO AND NOT
START TO GET INTO TOXICITY AND
WHAT IS GOING TO BE THE WAY IN
WHICH YOU DECIDE IF IT'S
WORKING?
WE NEED A BIOMARKER.
YOU'LL HEAR ABOUT ONE FROM
LESLIE.
YOU HEARD ABOUT PULSE WAVE
VELOCITY AND DIAGNOSTIC
FUNCTION.
YOU HAVEN'T HEARD ABOUT THE
CARDIAC SIDE OF PROGERIA AND
THERE'LL BE MEASURABLE
PHYSIOLOGIC CHANGE YOU COULD
ASSESS AND THERE'S
MANUFACTURING.
WHO WILL MAKE THE DRUG.
AND YOU GET ATTENTION AND THIS
IS NITTY-GRITTY STUFF AND MOST
ACADEMICS DO NOT HAVE THAT
EXPERIENCE, I CAN TELL YOU.
YOU NEED OTHER EXPERTS TO FIND
YOUR WAY INTO THAT YOU CAN MAKE
YOUR APPLICATION AND SAY I WANT
TO START A FIRST IN HUMAN TRIAL
AND THEY'LL TELL YOU YES OR NO
AND COME BACK WITH MORE DATA
LATER WHICH IS ALWAYS A CONCERN.
THAT'S WHERE WE ARE AND AT THE
SAME TIME LET'S TRY EVERYTHING
WE THINK MIGHT WORK AND TRY TO
FIX THAT MUTATION.
NOW, THIS IS CRAZY TO IMAGINE
THE POSSIBILITY OF SOMETHING
LIKE THAT.
IF YOU TOLD ME 10 OR 15 YEARS
AGO WE'RE ALREADY WORKING ON
PROGERIA YOU WILL BE IN ANOTHER
DECADE OR SO DESIGNING A TRIAL
THAT WILL ACTUALLY GO IN AND
EDIT THAT MUTATION IN VIVO IN
APPROPRIATE TISSUE I WOULD SAY
THERE'S NO WAY THAT COULD HAPPEN
IN MY LIFE TIME OR ANYBODY EL
ELSE'S THAT'S WHAT HAPPENED.
CRISPR HAS THE OPPORTUNITY TO
FIND AND REPLACE IN YOUR GENOME
WORD DOCUMENT AND THAT'S
BASICALLY WHAT WE ARE TRYING TO
DO IN THE CIRCUMSTANCE.
YOU'RE KNOCKING SOMETHING OUT
AND DOING A DOUBLE STRANDED
BREAK.
THAT'S NOT WHAT WE WANT TO DO
HERE.
YOU HAVE A TOXIC PROTEIN THAT
HAS A C TO A T YOU WANT TO
CONVERT THAT T BACK TO A C OR
THINK ABOUT IT ON THE OTHER
STRAND CONVERT AN A TO A G.
WHAT YOU DO NEED TO DO THAT?
YOU NEED A DEOXYADENOSINE
DEAMYLASE AND THIS IS WHERE
WE'VE HAD GOOD FORTUNE IN A
RELATIONSHIP THAT BEGAN IN THE
CLINICAL CENTER WHEN DAVID LU
CAME TO GIVE A TALK AS PART OF
THE WEDNESDAY AFTERNOON LECTURE
AND TOLD ME HE'D BEEN WORK A
LITTLE BIT ON PROGER YA AND BY
THE END OF THE AFTERNOON WE
STARTED A COLLABORATION WHICH
CONTINUES TO THIS DAY.
THIS IS THE APPROPRIATE GENE
EDITOR.
WE FIGURED THE SYSTEM IS AAV AND
AAV9 A PARTICULAR VERSION OF
THAT VIRUS AV9 HAS A PACKAGING
LIMIT AND WHEN YOU TRY TO FIGURE
OUT HOW YOU'RE GOING TO PUT INTO
THAT VIRUS ALL THE APPARATUS YOU
NEED TO DO THIS SPECIFIC
ADENOSINE EDIT AND NEED THAT
COMPLICATED SET OF SKIGGSQUIGGLD
MOLECULES AND INSTEAD THEY CAME
UP WITH THIS CLEVER APPROACH OF
HAVING TWO SEPARATE AAVs.
EACH OF WHICH HAS PART OF WHAT
YOU NEED BUT DESIGNED IF THEY
GET IN THE SAME CELL THE WHOLE
THING ASSEMBLES ITSELF PROPERLY.
I THOUGHT THIS WAS AWFULLY LIKE
YOU HAVE TO GET THE SAME CELL
INFECTED BY TWO VIRUSES AND LOOK
WHAT HAPPENED.
THIS IS MICE INJECTED
INTRAVENOUSLY WITH THE DOUBLE
AAV CONSTRUCT AND THEN LOOKING
TO SEE WHAT HAPPENS AT SIX WEEKS
OR AT SIX MONTHS IN TERMS OF
CORRECTING THE SINGLE NUCLEOTIDE
CHANGE.
HARVEST TISSUES, DO THE PCR AND
SEQUENCE WHAT'S THERE.
THE LIVER ALWAYS GETS THE BEST
RESULT BECAUSE LIVER LOVE
ANYTHING YOU INJECT
INTRAVENOUSLY SOMETHING LIKE 60%
OF THE CORRECTION HAPPENED.
EVEN IN PLACES WE CARE A LOT
ABOUT, THE HEART AND THE AORTA,
YOU'RE UP IN THE RANGE OF ABOUT
20% WHICH IS PRETTY GOOD, PRETTY
AMAZING FOR A SINGLE INJECTION
OF A VIRUS.
SO WE'RE PRETTY EXCITED.
THIS GETS US TO A PAPER IN
NATURE AND THAT'S THREE YEARS
AGO.
THERE'S A LOT OF WORK YET TO DO
THOUGH IT FELT LIKE OKAY, LET'S
TO PATIENTS NEXT.
THE CORRECTION OF THIS ALSO
RESULTED IN SUBSTANTIAL
LONGEVITY.
THAT WAS MORE EXCITING.
AGAIN ON THE LEFT YOU CAN SEE
THE SAME KIND OF RESULTS ABOUT
THE PERCENT OF CORRECTION.
YOU CAN SEE THE WESTERN BLOT
SHOWING WHAT'S HAPPENED AND THE
AORTA IN TERMS OF THAT PROGERIN
WHICH IS LIKE GONE ALMOST.
AND SOME MICE LIVING TO THE SORT
OF NORMAL AGE RANGE AND SORRY
THE VIDEOS DON'T WORK BECAUSE IF
I COULD RUN THEM YOU'D SEE THE
UNTREATED CONTROL MOUSE IS
LOOKING VERY SICK AND NOT MOVING
AROUND AND THE TREATED MICE ARE
RUNNING AROUND HAVING A GOOD
TIME.
AGAIN, DRAMATIC RESULT FROM A
SINGLE INJECTION.
ONE THING THAT HELPED US HERE IS
THINK ABOUT WHAT'S HAPPENING IF
YOU HAVE NOT CORRECTED ALL THE
CELLS IN THE AORTA OF THE HEART
THE ONCE YOU DIDN'T CORRECT WILL
SENESCE AND THEY'RE FADING AWAY.
THE ONES YOU DIDN'T CORRECT ARE
FINE AND IF THEY HAVE MORE
REPLICATIVE CAST HAVE YOU THIS
IN VIVO SELECTION WORKING FOR
YOU SO YOU DON'T HAVE TO HEAL
100% IN THIS SITUATION TO GET A
STRONG RESULT.
IN FACT WHEN WE LOOK
MICROSCOPICALLY OF THOSE ANIMALS
IT LOOKS LIKE IT'S HARD TO FIND
A CELL IN THE VASCULAR SMOOTH
MUSCLE COMPARTMENT MAKING
PROGE
PROGERIN.
THIS GOT PUT OUT AS AN EXAMPLE
OF SOMETHING THAT MIGHT PARTLY
LY -- POTENTIALLY TRANSLATABLE
INTO A HUMAN TRIAL BUT LOTS OF
THINGS TO THINK ABOUT.
WHERE ARE WE WITH THIS?
THERE'S AN ISSUE WITH THE DOUBLE
AAV PLAN.
IN ORDER TO GET HIGH ENOUGH
EFFICIENCY OF GETTING BOTH
VECTORS INTO THE SAME CELL YOU
HAVE TO GIVE A HEAVY LOAD OF
VIRUS AND WE KNOW FROM OTHER
HUMAN TRIALS WITH AAV9 OR OTHERS
THERE'S RISK OF TOXICITY IF YOU
GO FIVE TIMES 10 TO THE 15th
VIRAL KILOGRAMS TROUBLE STARTS
TO HAPPEN AND IF YOU'D LIKE TO
LIMIT THAT YOU WANT THE SINGLE
VECTOR AND NOT THE DOUBLE
BECAUSE YOU OUT TO BE ABLE TO
GET AWAY WITH THE LOWER DOSE.
THAT'S ONE THING.
COME BACK TO THAT IN A SECOND.
OTHER, YOU HAVE TO DO IT ALMOST
AT BIRTH TO GET A POSITIVE
RESULT.
WHAT IF YOU WAIT UNTIL THE MICE
GET A LITTLE BIT SICK?
COULD YOU IN FACT EXTEND THEIR
SURVIVAL AND SHOW BENEFIT?
WE'VE DONE AN EXPERIMENT WHICH
IS STILL IN THE WORKS OF BEING
ANALYZED AND WAITING UNTIL FOUR
MONTHS AT WHICH TIME THESE MICE
ARE PRETTY SICK AND INJECTED
THEM AND I THINK IT'S PRETTY
CLEAR THE CORRECTION STILL WORKS
PRETTY WELL.
THE RNA STILL WORKS PRETTY WELL.
WE'RE STILL DOING THE PATHOLOGY.
AND WE'VE HAD GREAT PARTNERS AND
IN MY LAB IN THE ROOM WE'VE
WORKED TIRELESSLY ON THIS AND
OTHER PROGERIA EFFORT.
THEY HAVE FIGURED OUT BY PICKING
THE RIGHT KAS 9 MORE CONSTRAINED
IN SIZE AND REENGINEERING THE
EDIT BASE EDITOR SO IT'S NOT SO
BULKY YOU CAN SQUEEZE THIS INTO
A SINGLE AAV AND THEY HAVE NOW
SENT THREE VERSIONS WITH THREE
GUIDE RNAs AND IN RECENT DATA IT
LOOKS AS IF THOSE WORK JUST
ABOUT AS EFFICIENTLY AS THE
DOUBLE AAV WHICH IS VERY
EXCITING.
SO I THINK IF WE'RE TALKING
ABOUT NOW GOING FORWARD TO HUMAN
TRIAL WE MAY HAVE OUR DRUG AND
DIDN'T UNTIL WE GOT TO THIS
POINT.
WE STILL NEED TO GO BACK IN WITH
THE SINGLE VECTOR AND MAKE SURE
IT REALLY WORKS LIKE THE DOUBLE
DID WE ALSO ARE STICKING WITH
AAV9 BECAUSE IT SEEMS TO HAVE
THE RIGHT PROPERTIES BUT NOT
IDEAL.
THERE'S A WHOLE WORLD OF NEW
CAPSIDS OUT THERE TRYING TO
FIGURE OUT WHETHER THERE'S
SOMETHING BETTER AND SOMETHING
THAT WOULDN'T COST US FIVE YEARS
IN TERMS OF GETTING IT THROUGH
THE FDA.
THIS ALREADY MADE IT THROUGH THE
REGULATORY PROCESS.
JUST LIKE WITH THE RNA AND DOSE
DETERMINATION AND TOX STUDIES,
AND WE HAVE TO FIGURE OUT WHAT'S
GOING TO BE THE RILE END POINT
IT BETTER NOT BE LONGEVITY AND
QUICKER AND THE FDA APPLICATION.
WE HAVE TWO TRIALS COMPETING
WITH EACH OTHER SIDE BY SIDE FOR
A RARE DISEASE AND SOME PEOPLE
MAY SAY AREN'T YOU OVERDOING IT?
NO, I THINK WE WANT TO MAKE SURE
WE SOMEWHERE SOMETHING THAT
WORKS AND BOTH HAVE POTENTIAL
AND BOTH CAN RUN INTO SOMETHING
UNEXPECTED THAT COULD SET US
BACK.
THAT'S WHERE I WANTED TO TAKE IT
AND BACK TO LESLIE.
LESLIE: WE DON'T SEE IT UNTIL
IT'S ALL CONCENTRATED IN THE ONE
TALK.
AS FRANCIS SAID IT TOOK US LIKE
10 YEARS OF CONTINUOUS
LONAFARNIB AND WE HAVE
POTENTIAL.
IF YOU LOOK AT THE GRAPH BEING
HERE'S LONAFARNIB EXTENDING IT
25% AND THAT TRANSLATED INTO THE
HUMAN.
HERE'S THE SMALL MOLECULE AND
THE DNA AND THERE'S NO REASON TO
THINK THIS COULDN'T HAPPEN IN A
HUMAN AS WELL.
THE MICE LIVED INTO OLD AGE.
PEOPLE SAY OH, THAT'S A MOUSE.
HOW DO YOU LEAP FROM A MOUSE TO
HUMAN.
WE DIT HERE AND HOW DO YOU DO IT
IN THE FUTURE AND IT TAKES
TRYING.
WHAT ARE WE GOING TRY IN THE
CLINICAL TRIAL AS AN EFFICACY
OUTCOME?
YOU HAVE TO KNOW IF THE DRUG
WORKS AND IF IT DOESN'T YOU HAVE
TO KNOW THAT TOO AND AS FAST AS
POSSIBLE BECAUSE I WANT TO GET
TO THE NEXT THING BECAUSE
TOXICITY IS THERE.
YOU DON'T WANT TO DO A DRUG
TRIAL FOR TOO LONG.
YOU WANT TO EVALUATE AND MOST
WILL BE FIRST IN HUMAN AND THE
CHALLENGES TO GET GREATER WITH
ALL THIS LONG LIST OF THINGS
FRANCIS HAS BEEN TALKING ABOUT.
IT'S QUITE AN ADVENTURE.
PUT IT THAT WAY.
WE'VE DEVELOPED A BIOMARKER.
WE DISCOVERED, LOOKED AND
DISCOVERED PROGERIN IS IN THE
BLOOD.
IT'S IN THE PLASMA AND DEVELOPED
A BIOMARKER AN OUTCOME MEASURE
AND LOOKED AT CHILDREN WITH THIS
IN THE LOG SCALE AND THE REST OF
US.
LOW HERE AND HIGH HERE.
WE HAVE SOMETHING HIGH
QUANTITATIVE AND IF WE LOOK DOWN
HERE, THIS BAR IS SHOWING YOU
THERAPY AND ALL THE BARS OVER 10
YEARS, THIS IS SHOWING
LONAFARNIB THERAPY.
YOU HAVE A DIP TO ABOUT HALF AND
THEN PRETTY MUCH A STEADY STATE.
IT STAYS LOW AND THAT IS GOING
TO BE REALLY IMPORTANT.
THIS WILL HELP ASSESS THE NEXT
DRUG BECAUSE IF IT WAS GOING
BACK UP WE'D HAVE A DIFFERENT
SITUATION THAN HERE AT A STEADY
STATE OF LOW.
WE SHOWED WHEN YOU LOOK AT
LENGTH OF TREATMENT AND THE
AMOUNT OF YOU DECREASE, THE GRAY
BAR SHOWS THE AVERAGE DECREASE
IN THE CHILDREN IN THE TRIAL AND
YOUNG ADULTS OF 15,000
PICOGRAMS PER MILL AND THE
LONGER YOU GO AND THE LONGER YOU
STAY LOW THE GREATER THE
BENEFIT.
THIS IS THE INCREASE IN LIFE
EXPECTANCY.
LOOK AT THIS AFTER 10 YEARS,
WHICH WE SURPASSED IN MANY KIDS,
WE'RE TALKING ABOUT ALMOST SEVEN
YEARS.
BACK TO YOU.
FRANCIS: BEFORE TELLING YOU THE
WHOLE STORY AND YOU CAN SEE
WE'RE ALL COMPELLED BY WHAT WE
CAN STILL DO IN THE NEXT STEPS
BUT ALSO THIS IS SUPPOSED TO BE
REPRESENTED AS AN EXAMPLE OF
SOMETHING THAT COULD BE
HAPPENING FOR LOTS OF OTHER
DISEASES.
THESE ARE THE DISORDERS FOR
WHICH WE KNOW THE EXACT MUTATION
AND I NEED TO UPDATE THIS
BECAUSE THIS IS THREE YEARS OUT
OF DATE BUT THE BARS KEEP GOING
UP.
IT'S ABOUT 7,000 CONDITIONS.
HOW MUCH WILL THOSE HAVE AN
EFFECTIVE TREATMENT?
PROGERIA IS ONE BUT THERE'S AN
AWFUL LOT OF THOSE STILL WAITING
EVEN THOUGH THEY HAVE FOR
DIAGNOSTIC PURPOSES A LOT MORE
KNOWN.
ONE REASON I'M EXCITED ABOUT
PURSUING THIS IN GENE EDITING
FOR PROGERIA BECAUSE IT FEELS
LIKE THE KIND OF APPROACH THAT
COULD BE SCALED TO LOTS OF
DISEASES IF WE CAN FIGURE OUT
HOW TO DO IT SAFELY AND
EFFECTIVELY.
YOU NEED THE RIGHT EDITOR AND
DELIVERY AND GOING TO THE TISSUE
AND ALL THAT NEEDS TO BE SAFE
AND YOU CAN BEGIN TO SOMETHING
GOING AFTER LOTS AND LOTS OF
THESE CONDITIONS WITHOUT HAVING
TO SPEND 10 OR 20 YEARS FIGURING
OUT THE PRECISE NATURE OF THEIR
MOLECULAR BIOLOGY AND FIX THE
MUTATION.
IT GETS HARDER WHEN YOU'RE
TALKING ABOUT TISSUE TO BRAIN
AND A LOT OF THESE ARE
CONDITIONS FOR WHERE THE BRAIN
IS INVOLVED BUT WE'RE STARTING
TO SEE SUCCESSES WITH IN VIVO
APPROACHES.
I GUESS WE OUGHT TO REFLECT AT
THE END OF THIS PRESENTATION
MORE BROADLY ABOUT WHAT THE
LESSONS FROM PROGERIA MIGHT MEAN
FOR THESE OTHER CONDITIONS
BECAUSE I THINK THERE'S BOTH
ENORMOUS EXCITEMENT
SCIENTIFICALLY AND ALSO A LOT OF
CONCERN HOW QUICKLY WE'LL BE
ABLE TO GET THIS DONE BECAUSE
WE'RE TALKING ABOUT ULTRA RARE
DISEASES.
YOU WON'T SEE PHARMACEUTICAL
COMPANIES SAYING I'LL SPEND $100
MILLION ON A CONDITION THAT ONLY
AFFECTS 30 PEOPLE.
WE HAVE AN ISSUE IN HOW TO SCALE
THIS IN A WAY THAT'S AFFORDABLE.
PRE CLINICAL AND CLINICAL COSTS
AS WE'RE TRYING TO DO NOW AND
TRYING TO FIGURE IT OUT HOW TO
COBBLE IT TOGETHER WITH THE
PROGERIA FOUNDATION AND ALL THE
EFFORTS THAT HAVE REQUIRED
SUPPORT WHERE DONORS HAD TO COME
UP.
THIS IS EXPENSIVE STUFF.
AND DO RUN ALL THE WAY FROM
BEGINNING TO END WE'RE TALKING
ABOUT TENS AND I THINK LESLIE
SAID IT'S CLOSER TO 100 TO DO
THIS.
WHERE'S IT ALL COME FROM IF THE
TRIAL IS FOR A RARE DISEASE
SEEKING TO ENROLL A SIGNIFICANT
FRACTION OF THE PEOPLE WHO HAVE
THE DISEASE.
SUPPOSE YOUR TRIAL WORKS AND YOU
CURE THEM ALL, WELL, THE MARKET
JUST GOT SMALL BUT IN THE LAST
TWO TO THREE YEARS AFTER INITIAL
ENTHUSIASM AND THERE'S DISEASES
LIKE DUCHENNE'S AND THERE'S NOT
A LOT OF INTEREST IN THE PRIVATE
SECTOR IN MAKING INVESTMENT.
SO WHAT DO WE DO?
OUR COLLEAGUES AT THE FDA ARE
TRYING TO STEP BACK FROM
UNNECESSARY LEVELS OF CONSTRAINT
ON HOW YOU CAN GET STARTED WITH
THE TRIAL PARTICULARLY A BIG
SHOUT OUT TO PETER MARKS AS A
LEADER IN THAT SPACE AND COMING
UP WITH WAYS MAYBE WITH
TEMPLATES SO WHEN YOU BRING
SOMETHING FORWARD IT'S NOT THE
42 BOXES OF MATERIAL THAT IN THE
PAST OFTEN TIMES WERE NECESSARY
BEFORE YOU COULD START THE
CONVERSATION.
NIH IS THE BESPOKE CONSORTIUM
AND THIS IS ONE OF THE
ACCELERATING MEDICINES
PARTNERSHIPS I HAD A CHANCE TO
START A FEW YEARS AGO AND
THEY'RE ALSO EXPLORING THE SAME
WAYS OR WAY TO DO THIS AT LOWER
COST AND MORE EFFICIENCY AND
MAKING SOME PROGRESS BUT NOT TO
THE POINT OF HAVING ANYWHERE
NEAR SOLVE THE ISSUE.
PHILANTHROPY IS GOING TO BE
CRITICAL BUT I DON'T THINK
THERE'S ENOUGH FOR THESE
DISEASES TO CALL THAT THE ANSWER
AND MAYBE THE NEW KID ON THE
BLOCK ARPA-H WHICH WAS STARTED A
COUPLE YEARS AGO MAY SEE THIS AS
ONE OF THOSE GAME-CHANGING
MOMENTS WHERE SOME INITIAL
INVESTMENTS TO CREATE A PLATFORM
FOR THESE KINDS OF RARE DISEASE
AND THERE'S A SIGNIFICANT
CHALLENGE HERE THAT HAS NOT YET
BEEN FULLY APPRECIATED OR
SOLVED.
SO FINALLY TO WIPE THIS OUT, I
THINK I WANT TO TAKE A MINUTE TO
REFLECT ON HOW REMARKABLE THIS
EXPERIENCE HAS BEEN AND ALONG
THE WAY WE'VE BEEN JOINED BY
OTHER REMARKABLE FOLKS AND THIS
IS A SCREEN SHOT OF OUR MONDAY
LAB MEETINGS.
THIS IS FROM YESTERDAY THAT WE
HAVE PRETTY MUCH EVERY MONDAY AT
4:00 INVOLVING SAMMY, OUR
WONDERFUL HEROIC FIGURE AND
DAVID LU AND WE HAVE THE BEST
CHEERLEADER FOR OPTIMISM I'VE
SEEN IN A LONG TIME AND THIS IS
FIVE OF US BECAUSE IF REALLY
LOOKED AT ALL THE COLLABORATORS
ON THIS AND I COULD SPEAK TO ALL
THOSE IN MY LAB IN THE LAST 25
YEARS AND BOSTON CHILDREN'S
HOSPITAL AND ALL THOSE THAT MADE
THIS POSSIBLE AND THE NATURAL
HISTORY STUDY AND DAVID'S LAB
WITH HIS CONTRIBUTIONS AND
PEOPLE PART OF THE PROGERIA
RESEARCH COMMUNITY, THIS IS
REALLY A REMARKABLE EXPERIENCE.
>> IT'S WHAT YOU SAID, EVERY
MONDAY.
HOW MANY YEARS HAVE WE BEEN AT
THIS?
SIX YEARS.
WE'RE STILL MEETING EVERY MONDAY
AND IT'S A SLOG.
IT'S DIFFICULT.
NOTHING -- EVERYBODY IN THE
ROOM, NOTHING ABOUT SCIENCE IS
IT'S DIFFICULT BUT COMPLETELY
WORTH IT.
SAMMY, HE'S ONE YEAR WITH THIS
GROUP A COUPLE YEARS AGO.
>> IT'S 11:30 AT SAMMY'S HOUSE
RIGHT NOW.
>> SAMMY, DO YOU WANT TO SAY
ANYTHING ABOUT THHIS?
CAN YOU SEE THIS PHOTO FROM
YESTERDAY?
>> I DON'T WANT TO BE RUDE BUT
I'M PROUD TO BE PART OF THIS
GROUP.
MY FIRST --
>> THERE'S A 30-SECOND DELAY NO
PROBLEM.
>> OKAY.
IT'S BEAUTIFUL TO BE PART OF
THIS GROUP BECAUSE FIRST IT WAS
ABOUT CRISPR CAS 9 AND NOW I'M
COLLABORATING WITH THEM AND YOU
WITH PERFORMING THE NEW
TECHNIQUE FINALLY, LESLIE, I CAN
UNDERSTAND WHAT YOU'RE TALKING
ABOUT SCIENTIFICALLY AND
FRANCIS, WHEN YOU ASK ME WHAT DO
YOU THINK BIT I'M ALWAYS MIND
BLOWN BECAUSE I THINK IF FRANCIS
WANTS MY OPINION I'M DOING A
GOOD JOB.
IT'S INCREDIBLE TO SEE THE
EFFORT OF EVERYONE.
THIS IS WHAT IT MEANS FOR ME TO
BE A COMMUNITY AND IT IS NOT
JUST ABOUT MY DISEASE RIGHT NOW
BECAUSE I KNOW GENETIC THERAPY
WILL NOT BE FOR ME BECAUSE I'M
28.
I CAN HELP WITH THIS BUT IT IS
NOT FOR ME BUT FOR THE NEW
GENERATIONS, NOW I CAN SAY AS A
SCIENTIST THERE'S PROGERIA GAVE
ME A REASON OF LIFE AND I'M
SEEING SO MANY PEOPLE SAD
BECAUSE THEY'RE NOT REASON AND
I'M LUCKY TO HAVE A REASON OF
LIFE.
>> THANK YOU, SAMMY.
>> I THINK YOU ALSO ECHOED SOME
OF THE MOST REMARKABLE
STATEMENTS FROM YOUR FRIEND SAM
AND IF PEOPLE HAVE NOT HAD THE
CHANCE TO LEARN LIFE ACCORDING
TO SAM IT'S SOMETHING EVERYBODY
SHOULD TAKE TIME TO WATCH YOUR
FAMILY.
SAM, HIS PHILOSOPHY FOR A HAPPY
LIFE WAS IN A TED X THAT HAD
MORE THAN 100 MILLION DOWNLOADS.
>> 100 MILLION VIEWS AND EDGED
OUT BILL GATES, JUST WANT TO
SAY.
>> HE HAD A SET OF
RECOMMENDATIONS, FOUR OF THEM.
BE OKAY WITH WHAT YOU ULTIMATELY
CAN'T DO BECAUSE THERE'S SO MUCH
YOU CAN DO.
SURROUND YOURSELF WITH PEOPLE
YOU WANT TO BE AROUND, KEEP
MOVING FORWARD AND YOU THINK
THAT SEEMS TO COVER IT ALL.
WHAT'S NUMBER FOUR?
NEVER MISS A PARTY IF YOU CAN
HELP IT AND THAT'S THE WAY SAM
LIVED HIS LIFE AND I KNOW HE
WOULD WANT ALL OF US TO DO THE
SAME.
THAT'S KIND OF WHERE WE WANTED
TO BRING THIS TO THE POINT MAYBE
OF QUESTIONS IF THERE ARE SOME.
THERE ARE SOME WE COULD HEAR
ABOUT BEFORE WE LET EVERYBODY
FADEAWAY FROM HERE.
>> I WANTED TO REMEMBER PEOPLE
ONLINE A LOT OF PEOPLE OUTSIDE
THE NIH WATCHING THERE'S A SEND
LIVE FEEDBACK BUTTON NOT
INTUITIVE TO ASK QUESTIONS BUT
THAT'S HOW YOU ASK QUESTIONS AND
THEY COME TO US IN THE ROOM.
>> WE DO HAVE SOME PROVOCATIVE
AND INTERESTING --
>> THERE'S PEOPLE IN THE ROOM
ALSO.
>> ANYONE IN THE ROOM?
>> PLEASE GO TO THE MICROPHONE
IF YOU HAVE -- SO
>> SAM'S VERY BRIGHT, VERY
INTELLIGENT.
A LOT OF THE STUFF YOU'RE
TALKING ABOUT WITH THE CLASSIC
STROKES AND CARDIOVASCULAR IERZ,
I NOTICED YOU GUYS WEREN'T
TALKING ABOUT NEUROLOGICAL
PATHOLOGIES.
WHY IS THAT?
FRANCIS: YOU'RE RIGHT, DIM EN IS
THAT DOESN'T SEEM TO BE PART OF
THE CONDITION BUT STROKES CAN BE
PART OF THE NEUROLOGICAL
PROBLEM.
LES
LESLIE: PROGERIN IS EXPRESSED IN
THE VASCULATURE OF THE BRAIN BUT
NOT THE BRAIN.
SOME BEAUTIFUL WORK PUBLISHED
YEARS AGO DISCOVERED MICRORNA
THAT EXPRESSES PROGERIN IN THE
BRAIN.
THE BRAIN AND THE NEUROLOGICAL
SYSTEM ARE NORMAL.
LIVER FUNCTION, KIDNEY FUNCTION,
IMMUNE FUNCTION AND
GASTROINTESTINAL FUNCTION ARE
NORMAL WHICH HELPS US A LOT
CLINICAL TRIALS.
AS A CONSEQUENCE OF COURSE,
THEY'RE ALL BRILLIANT, JUST
SAYING.
>> IF YOU PULL DOWN THE SLIDE --
HOW WOULD YOU SUGGEST WE PULL
DOWN BECAUSE I'M AFRAID WE'LL
HIT THE WRONG BUTTON.
>> LAMIN A SOUNDS LIKE THE
MAINLY PLAYER.
HAVE YOU LOOKED AT ANY OTHER
POSSIBLY CONTRIBUTING TARGETS OR
HAS LAMIN A JUST BEEN IT?
>> THERE'S PROGEROID SYNDROME
AFFECT OTHER PARTS OF THIS
PATHWAY.
THE ENZYME I MENTIONED THAT DOES
THE CLEAVAGE, IF THAT'S NOT
PRESENT IT GIVES A RATHER SEVERE
SOMETHING CALLED RESTRICTIVE
DERMOPATHY WITH HAS OVERLAP
BECAUSE YOU DON'T DO THE
CLEAVAGE AND HAVE LAMIN A
BECAUSE THE ENZYME WASN'T THERE
TO HELP IT I JUST READ A PAPER
LAST NIGHT THERE'S A PATIENT
DESCRIBED AS A POINT MUTATION IN
THAT AND THERE'S A LAMINOPATHY
THAT LOOKS LIKE A MILDER VERSION
AND IT WORKS A LITTLE BIT.
AND THERE'S SIMILAR TYPES AND A
CURATOR OF MOST OF THOSE.
>> IN ADDITION YOU'RE TALKING
ABOUT DOWN STREAM TARGETS
BECAUSE YOU HAVE SO MANY DOWN
STREAM AND WHICH ARE IN REASON
TO THE PATHOLOGY AND WHAT WILL
YOU HIT IF YOUR DRUG IS DOWN
HERE?
A LOT OF DISEASES HAVE
TREATMENTS THAT ARE EFFECTIVE
DOWN STREAM BECAUSE THEY CAN'T
CORRECT THE GENE.
WE'RE TALKING ABOUT THE RNA AND
DNA THERAPIES AND THERE'S A LOT
OF EXPRESSION PROFILES HAVE BEEN
DONE I'M SURE THEY'RE THERE BUT
IT'S TOUGH STUFF.
WHAT ARE THE IMPLICATIONS FOR
AGING IN THE GENERAL POPULATION
BASED ON THE RESEARCH FINDINGS
AND CLINICAL TRIALS.
>> WE'RE PLANNING TO PUT THE
MEDICATION IN THE WATER.
PEOPLE WONDERED WILL PROGERIA
TEACH US SOMETHING ABOUT NORMAL
AGING OR IS IT A DRAMATIC
PHENOCOPY.
IT HAS A CONNECTION AND THE
NATURE OF THE CRYPTIC SPLICE
DONOR.
WOULD IT BENEFIT US TO BE ABLE
TO KNOCK THAT BACK AND SEE?
YOU CAN MUTATE THE NUCLEOTIDES
SO WE'RE CURIOUS TO SEE DOES THE
MOUSE LIVE FOREVER OR LIVE
LONGER THAN A WILD TYPE MOUSE OR
ALTERNATIVELY, THINK ABOUT THIS,
IT DOES SEEM LIKE THIS IS PART
OF PROGRAM SENESCENCE.
THIS IS NOT AN ACCIDENT.
CELLS HAVE A MECHANISM WHEN
THEY'RE JUST ABOUT DONE TO BE
REALLY DONE AND TO HEAD TO THE
EXIT AND YOU CAN SOMETHING WHAT
THAT MIGHT BE.
WILL THE ANIMALS HAVE A HIGHER
RISK OF CANCER?
I DON'T KNOW.
WE NEED TO UNDERSTAND THAT
BETTER.
CERTAINLY IT IS FAIR TO SAY WHAT
WE'VE LEARNED ABOUT PROGERIN HAS
SHED A LOT OF IMPORTANT LIGHT ON
THE NORMAL AGING PROCESS NOT YET
TO THE POINT OF SAYING HERE'S
WHAT WE SHOULD DO ABOUT IT BUT
HOW TO UNDERSTAND IT SO THE
AGING INSTITUTE WHICH HAS BEEN A
BIG SUPPORTER OF EXTRAMURAL
SUPPORT IN PROGERIA HAS BEEN A
GREAT PARTNER.
>> THEY'VE SUPPORTED A LOT OF
OUR SCIENTIFIC MEETINGS.
THERE'S ELEGANT STUDIES DONE TO
START TO GET AT THE QUESTION.
PROGERIN IS EXPRESSED IN ALL
LAYERS AND INCREASES AT 3% PER
YEAR IN THE VASCULATURE AND
FREQUENCY.
THERE WAS A STUDY ON HUMAN
BIOPSIES AND LOOKED FOR PROGERIN
AND IF YOU LOOKED AT A
6-YEAR-OLD AND 7-YEAR-OLD AND
BY THE TIME TO 80 OR 90 YEARS
OLD THERE WERE CELLS ALL OVER
THE SKIN WITH PROGERIN
EXPRESSION.
IT BUILDS UP WITH AGE.
IT'S THERE.
WHAT IT MEANS AND IF YOU
MANIPULATE IT TO THE BENEFIT OF
SHOULD BE AN AREA OF STUDY.
>> WHAT SYMPTOMS USUALLY BRING A
PROGERIA PATIENT TO CONSULT AND
DO WE KNOW WHAT PLASMA PROGERIN
IS FROM THE STANDPOINT OF IT
BEING DIAGNOSTIC?
>> WHEN SAM WAS FIRST DIAGNOSED
IT TAKES -- PARENT OF KIDS WITH
RARE DISEASES KNOW THIS YOU GO
FROM DOCTOR TO DOCTOR AND TEST
AFTER TEST.
BUT NOW PROGERIA IS IN
HARRISON'S, IT'S IN TEXTBOOK AND
TAUGHT IN MIDDLE SCHOOL AND
MEDICAL SCHOOL.
IT WASN'T TAUGHT BACK THEN AND
KIDS ARE DIAGNOSED EARLIER AND
THE SKIN SIGNS -- THERE ARE SKIN
SIGNS DERMATOLOGISTS ARE VERY
VISUAL PEOPLE SO SKIN SIGNS ARE
OFTEN SOME OF THE FIRST SIGNS.
GROWTH FALLS OFF TOO AND THAT
COULD BE THE FIRST SIGNS BUT THE
EARLIER KIDS, IT'S THE SKIN
SIGNS.
WHAT WAS THE SECOND QUESTION?
>> WE WANT VALIDATED FOR THE
CLINICAL TRIALS BECAUSE WE HAVE
A GENETIC TEST.
ABOUT 10% COME FROM MUTATION AND
IF YOU WANT TO KNOW WHAT'S GOING
ON, SEQUENCE THE GENE.
>> I CAME TO THE LECTURE NOT
BECAUSE I KNOW SOMEBODY WITH
PROGERIA OR BECAUSE FRANCIS IS
SPEAKING BUT THERE'S INTERESTING
IN THIS AND I WORK ON A FORM OF
HEPATITIS AND THERE'S AN ANTIGEN
AND THERE'S EFFORTS TRYING TO
TREAT DELTA VIRUS INFECTION AND
THERE COULD BE OTHER EXAMPLES OF
OTHER VIRAL INFECTIONS.
I'M INTERESTED IN YOUR
PERSPECTIVE IF THAT'S THE CASE
IS THAT A WORTHWHILE APPROACH TO
DEVELOP ANTIVIRALS TARGETING THE
CELLULAR PROCESS INSTEAD OF
ANTIVIRAL THERAPY.
>> IT'S A CRITICAL STEP IN THE
ABILITY TO INVADE THE NEXT CELL.
HAVE YOU THE SIDE EFFECTS THAT
WILL HAPPEN AND SAMMY COULD TELL
YOU WHEN HE FIRST GOT STARTED ON
LONAFARNIB IT WASN'T THAT
PLEASANT UNTIL YOUR BODY GETS
USED TO THEM.
THE REASON IT DIDN'T WORK FOR
CANCER OR RAS AND THIS GETS IN
THE NITTY-GRITTY, THERE'S
ANOTHER WAY OF ATTACHING A THIGH
HYDROPHOBIC TRAIL AND WITH RAS
YOU COULD DO BOTH AND LOOK AT
THE THIS AND --
>> THAT WAS THE PRIMARY
INTEREST.
THAT WAS THE HEPATITIS DELTA.
THAT DIDN'T GO AS PLANNED.
>> THERE'S OTHER PROCESS.
>> IF IT WORKED FOR PROGERIA IT
MAY WORK FOR SOMETHING ELSE.
>> LONAFARNIB DIDN'T GET MUCH
EXPERIENCE FOR OTHER THINGS AND
NOW IT'S FDA APPROVED.
>> THERE'S QUESTIONS WHETHER
PROGERIA IS AN INHERITED
DISEASE.
>> WE CALL IT OUT AUTOSOMAL
DOMINANT BUT HAS NEVER BEEN
INHERITED FROM A PARENT TO A
CHILD BECAUSE PEOPLE WITH IT
HAVE NOT PRODUCED AND IT'S DE
NOVO FROM THE WAY WE UNDERSTAND
THE EFFECT OF THE DOMINANT
NEGATIVE PROTEIN IF YOU WERE
ABLE TO REPRODUCE WITH THIS IT'D
BE A 50/50 CHANCE AND IT'S
CORRECT TO CALL IT AUTOSOMAL
DOMINANT BUT CONFUSES PEOPLE
ABOUT THE VERTICAL
TRANSMISSIONS.
WE'VE NEVER SEEN ONE BUT AT SOME
POINT MAYBE WE WILL.
>> WE ONLY HAVE A FEW MINUTES
LEFT AND I KNOW SAMMY HAD ASKED
TO ASK US A FEW QUESTIONS.
GO FOR IT, SAMMY.
>> YEAH, I HAVE TOO MANY
QUESTION.
THE FIRST IS HOW DO YOU DEAL
WITH THE FRUSTRATION WHEN THE
SCIENTIFIC RESULTS ARE NOT AS
EXPECTED.
THAT'S THE FIRST QUESTION BUT I
HAVE ANOTHER ONE.
>> OKAY, DRIVES ME OUT OF MY
MIND.
THE SCIENTIFIC RESULTS ARE WHAT
THEY ARE.
I KIND OF THRIVE ON THOSE.
IF YOU DO THINGS REALLY WELL AND
GET AN ANSWER ONE WAY OR
ANOTHER, IT LEADS YOU SOME
PLACE.
THE BUREAUCRACY, THE MONEY, THE
PACE WHEN YOU'RE TRYING TO SAVE
LIVES YOUR CHILD OR OTHERS,
CHILDREN, IT IS REALLY REALLY
DIFFICULT AND I DON'T KNOW YOU
JUST PUSH FORWARD AND PUSH OTHER
PEOPLE I'M A PUSHY GAL SO -- I
DON'T KNOW.
I DON'T KNOW HOW ELSE TO SAY IT.
IT'S JUST THE TRUTH BUT YOU HAVE
TO KEEP MOVING FORWARD.
THAT'S IT.
>> LESLIE, YOU PUSH PEOPLE BY
LURING THEM INTO THIS PROGRAM
AND THEN THEY NEVER LEAVE
BECAUSE IT'S TOO COMPELLING.
I THINK YOU SAID IT WELL.
THE OTHER THING I'D SAYING ABOUT
THE SCIENTIFIC FAILURE IS
THEY'RE INCREDIBLY DISAPPOINTING
AND DEVASTATING AND SAY TO
YOURSELF I HAVE TO LEARN
SOMETHING FROM THIS.
I HAVE TO FIGURE OUT WHAT
HAPPENED HERE AND HOW CAN I USE
THAT INFORMATION TO DESIGN THE
NEXT APPROACH THAT'S GOING TO BE
MORE SUCCESSFUL SO I'M FURTHER
ALONG THAN I WOULD HAVE.
>> I DON'T LIKE LOOKING BACK AND
SAYING I COULD HAVE DONE THAT
BETTER BECAUSE I DO THAT A LOT
BUT I TRY TO TURN THAT INTO IN
NOT LOOKING BACKWARDS BUT GO
FORWARD AND TRY TO PUSH THE
DIFFICULT PORTION DOWN A LITTLE
BIT.
WHAT'S YOUR SECOND QUESTION?
>> SECOND QUESTION IS ABOUT SAM.
OF COURSE SAM WAS MY FRIEND.
HE IS MY FRIEND I PREFER TO SAY.
AND YOU KNOW I SHOULD THANK GOD
FOR PROGERIA FOR PUTTING YOU AND
SAM IN MY LIFE AND SAM WAS ABLE
TO IMPACT THE LIFE OF SO MANY
PEOPLE.
IT'S BEAUTIFUL AND LIFE IS
GREAT.
I WANT TO TRUST YOU BOTH, WHAT
IS THE PART OF SAM'S MESSAGE
THAT IMPACTED YOU MORE AS A
MOTHER AND FRIEND BUT ALSO JUST
AS PEOPLE.
I KNOW IT IS A DIFFICULT
QUESTION.
>> IT'S A GOOD QUESTION BECAUSE
THERE'S A LOT OF FACETS OF THE
FRIENDSHIP I HAD WITH SAM I
COULD REFLECT ON AS HAVING LEFT
A REALLY IMPORTANT LIFE ON MY
WHOLE VIEW OF HOW MEDICAL
RESEARCH SHOULD BE CONDUCTED.
IT WAS -- IT WAS IMPATIENCE BUT
ALWAYS IN THE MOST GENEROUS WAY.
YOU CAN BE IMPATIENT AND
IRRITATING.
HE WAS IMPATIENT AND INSPIRED
YOU TO TRY TO FIGURE OUT HOW TO
GO FASTER AND DO THINGS BETTER
BUT ALSO HAD THIS WONDERFUL
INFECTIOUS WAY OF LOVING LIFE AS
YOU DO, SAMMY.
THE TWO OF YOU CARRY THAT
THROUGH ALL YOU'VE BEEN THROUGH
IN A REMARKABLE WAY THAT MAKES
YOU FEEL HOW CAN I COMPLAIN
ABOUT ANYTHING BECAUSE HERE'S
TWO YOUNG WHEN WHO COULD HAVE
DECIDED I'LL HIDE IN THE CORNER
AND INSTEAD HAVE BEEN UP THERE
WHETHER WITH 100 MILLION
DOWNLOADS ON A TED X OR YOU IN
FRONT OF I DON'T KNOW HOW MANY
PEOPLE IN PADUA INSPIRING THEM
TO THINK ABOUT WHAT THEY COULD
DO.
ALL OF THAT, I GUESS THAT ONE
QUOTE IN HIS FOUR STATEMENTS
ABOUT THE LESSONS FROM SAM,
DON'T FOCUS ON WHAT YOU CAN'T
DO, FOCUS ON WHAT YOU CAN.
HE LIVED THAT IN EVERY WAY.
HE WAS THE KID WHO WAS IN THE
MARCHING BAND FOR HIGH SCHOOL
EVEN THOUGH IT REQUIRED A
SPECIAL APPARATUS TO BE ABLE TO
DO SO, HE WAS NOT GOING TO PASS
THAT UP.
>> I'LL TELL YOU A STORY.
PHYSICIANS OFTEN GET CALLS FROM
FRIENDS WHO HAVE FRIENDS WHO
HAVE FRIENDS WHO NEED HELP.
THEY TRY TO GET THE BEST
DOCTORS, WHO DO YOU RECOMMEND
AND SO THIS HAPPENS A LOT AND WE
TAKE CALLS -- PHYSICIANS TAKE
CALLS FROM ONE ANOTHER A LOT TO
TRY TO HELP.
I GOT I CALL FROM A FRIEND WHO
HAD A FRIEND WHOSE SON IS 11 AND
HAS SOMETHING COMPLETELY
DIFFERENT FROM PROGERIA BUT HAS
HAD IT SINCE BIRTH AND NEEDED A
SURGERY, NEUROLOGIC TYPE OF
SURGERY AND THEY WERE NOT FROM
MASSACHUSETTS AND LOOKING
LOCALLY AND WANTED TO GET MY
THOUGHTS ON WHO WOULD BE GREAT
EITHER AT BOSTON CHILDREN'S OR
SOME PLACE ELSE.
I WAS TRYING TO HELP WITH THAT
AND TALKING TO MY COLLEAGUES.
SO I SPOKE TO THIS MOM AND SHE
TOLD ME A STORY THAT I WAS JUST
STUNNED BY.
THIS IS A COMPLETELY DIFFERENT
DISEASE PROCESS AND SHE SAID,
YOU KNOW, WHEN MY SON WAS BORN
YOUR SON'S TED TALK WAS WHAT GOT
US THROUGH.
WE WERE SO INSPIRED BY WHAT --
WE WERE SO DEVASTATED GOING
THROUGH SO MUCH AND WATCHED
SAM'S TED TALK AND GOT US
THROUGH AND COULD NOT BELIEVE I
WAS TALKING TO SAM'S MOM.
SOMEBODY SAID TALK TO LESLIE
GORDON AND CHAT WITH HER AND
TELL HER WHAT YOU NEED.
I WAS SO IMPACTED BY THAT
BECAUSE IT'S A RIPPLE AFFECT.
WE'VE BEEN TALKING ABOUT A
RIPPLE EFFECT AND WE GET THAT
TOO BUT JUST HIS RIPPLE AFFECTS,
I CAN'T IMAGINE IF IT REACHED
THAT WOMAN AND THAT FAMILY, WHO
ELSE HAS IT REACHED AND WHAT
ELSE HAS SAM DONE FOR THEM?
THAT MADE ME FEEL REALLY GOOD.
>> WE HAVE REACHED THE END OF
OUR TIME BUT I THINK ON BEHALF
OF EVERYONE HERE AND THE LARGE
NUMBER OF PEOPLE WHO HAVE
WATCHED AND WILL GO TO THE
ARCHIVE, WE CAN HARDLY THANK YOU
ENOUGH FOR NOT ONLY AN
INCREDIBLY CONCISE AND BEAUTIFUL
PRESENTATIONS BUT REALLY
EMPHASIZING THE IMPORTANCE OF
THESE RARE DISEASES AND THE
STRUGGLE THAT'S INVOLVED TO
BRING SOME RELIEF TO THESE
PATIENTS IF NOT CURE, AND
ENORMOUS EFFORT THAT'S REQUIRED
WHICH YOUR ORGANIZATION AND THE
FOUNDATION COUPLED WITH THE
RESEARCH EFFORTS AND NOW IT
BECOMES A WORLD ACTIVITY.
ONE ONLY HOPES THIS WILL CARRY
ON IN SOME WAY TO MANY OF THE
7,000 RARE DISEASES MOST OF
WHICH ARE DEVASTATING SO THANK
YOU.
THANK YOU VERY VERY MUCH FOR THE
MOST EXCITING AFTERNOON.
>> THANKS FOR INVITING US.
>> THANKS, EVERYBODY.
THANKS, SAMMY.
>> THANK YOU.