SO GOOD AFTERNOON MY NAME IS KEN
JACOBSEN IT IS MY GREAT PLEASURE
TO INTRODUCE TODAY'S WALS
SPEAKER, DANIELA SALVEMINI, I
WAS ASKED TO GIVE THE LECTURE
CODE 57679 AND ALSO THE END OF
THE LECT YOU YOU CAN ASK A
QUESTION IN PERSON OR SUBMIT A
QUESTION ONLINE USING THE "SEND
LIVE FEEDBACK BUTTON" ON THE
VIDEO PAGE.
FOLLOWING THE PRESENTATION THERE
WILL BE A RECEPTION OUTSIDE THE
OWDITORIUM.
SO DR. SALVEMINI IS A LONG-TERM
COLLABORATOR OF OURS AND I KNOW
HER EXCITEMENT RELATED TO
GCPRs.
SHE'S CURRENTLY THE WIMIAM
BEAUMONT CHAIR OF PHARMACOLOGY
AND PHYSIOLOGY.
FOUNDING DIRECTOR FOR
INSTITUTIONAL TRANSLATIONAL
SCIENCE AT ST. LOUIS UNIVERSITY,
DR. SALVEMINI RECEIVED HER BSC
IN PHARMACOLOGY AND Ph.D. FROM
UNIVERSITY THE LONDON.
SHE EARNED IT UNDER THE
MENTORSHIP OF PROFESSOR SHIRR
JOHN VAIN WHO WON THE NOBEL
PRIZE FOR ELUCIDATING EFFECTS OF
PROOF THE GLANDINS.
A LOST THINGS WE TAKE FOR
GRANTED NOW, WE HAVE TO STUDY
THE HISTORY.
SHE PURSUED POST DOCTORAL AT
LOPPED AN RESEARCH INSTITUTE AND
AT MONSANTO IN THE STOEVERY OF
PHARMACOLOGY BEFORE JOINING
ST. LOUIS UNIVERSITY HER
RESEARCH INTERESTS NEAR
UNDERSTANDING THE MOLECULAR
MECHANISMS INVOLVED IN
NEUROPATHIC PAIN STATES AND
DISCOVERY OF NONOPIOID
THERAPEUTICS, TO ADDRESS A MAJOR
UNMET MEDICAL NEED, AND HELP AND
HUMAN SUFFERING.
SHE SERVES UNDER NUMEROUS
COMMITTEES AND BOARDS INCLUDING
THE NIH STUDY SECTIONS AT NIDA,
NCI AND NINDS, SHE'S THE FOUNDER
OF 2 START UP COMPANIES: BY O
INTERVENE IS IDENTIFYING
RECEPTOR AGONISTS FOR
NEUROPATHIC PAIN AND
NEUROINFLAMMATORY DECS INVINCION
INCORPORATED THAT IS DEVELOPING
NOVEL THERAPIES FOR PAIN AND
CANCER.
SHE'S ALSO THE FOUNDER OF THE
ST. LOUIS TRANSLATIONAL PAIN
RESEARCH FORUM.
SHE'S HAD MANY AWARDS INCLUDING
THE NOVARTIS AWARD IN
PHARMACOLOGY, OUTSTANDING
SCIENTIST AWARD FROM THE
ST. LOUIS ACADEMY OF SCIENCE,
PHARMACY AWARD IN EXPERIMENTAL
THERAPEUTICS AND THE MITCHELL B
MAX AWARD FOR PAIN FROM THE
AMERICAN ACADEMY OF NEUROLOGY,
SHE'S A FELLOW OF THE ST. LOUIS
ACADEMY OF SCIENCE AND ALSO
FELLOW OF THE NATIONAL ACADEMY
OF INVENTORS AND ALSO THE FELLOW
RESEARCH INSTITUTE, FINALLY,
RECENTLY SHE WAS MADE A FELLOW
OF THE AMERICAN SOCIETY OF
FORMICOLOGY AND EXPERIMENTAL
THERAPEUTICS ASSPEC.
DR. SALVEMINI, HAS STUDY THE
SPHINGOPATHY AND I NOW INVITE
HER TO DELIVER THE LECTURE.
[ APPLAUSE ]
>> THAIRNG YOU -- THANK YOU VEY
MUCH DR. JACOBSEN AND ALL THE
ORGANIZERS AND IT'S A PLEASURE
TO BE HERE AND DELIVER THIS
LECTURE, SO FAR I HAD A
BEAUTIFUL DAY.
MET WITH WONDERFUL STUDENTS AND
PIs AND I'M LOOKING FORWARD TO
THE REST OF THE DAY SO AS
DR. JAIB OBSESSIVESSEN MENTIONED
WE ARE VERY MUCH INTERESTED IN
GPC Rs AND TODAY I WILL GIVE
YOU AN OVERVIEW OF 1 OF MY
FAVORITE PROJECTS THAT I STARTED
15 YEARS AGO IN ABOUT 45 MINUTES
SO I HAD TO KIND OF PICK AND
CHOOSE THE SLIDES THAT I WANTED
TO SHOW YOU TO CONVEY OUR
MESSAGE BUT REALLY THE TAKE HOME
MESSAGE HERE IS THAT I WOULD
LIKE TO PROPOSE THAT WE SHOULD
CONSIDER SOME TYPES OF
NEUROPATHIC PAIN CONDITIONS AS
SPHING OPEN MEETINGATHYS THAT
ARE THAT ARE TO THE THERAPIES
AND THIS IS REALLY MY STORY.
SO MOST OF YOU KNOW THAT CHRONIC
PAIN IS A DISEASE, CAN YOU SEE
MY POINTER?
IT IS 1 OF THE MOST SIGNIFICANT
HEALTH ISSUES IN THE GLOBE,
AFFECTS MILLIONS OF INDIVIDUALS
AROUND THE UNITED STATES
AFFECTING BILLIONS OF DOLLARS
EACH YEAR IN MEDICAL TREATMENTS,
CHRONIC PAIN IS ALSO LINKED TO
ANXIETY, DEPRESSION, OBESITY,
STRESS, SLEEP DISPUSHANCES AND
MECHANISMS REMAIN OBSCURE.
SO THE RESEARCH INTEREST IN MY
LABS ARE REALLY KIND OF STRAIGHT
FORWARD, WE WANT TO TARGET
CHRONIC NEUROPATHIC PAIN STATES
TO ADDRESS A BIG MEDICAL NEED.
WE WANT TO UNDERSTAND AND
DECIPHER MOST THE MOLECULAR AND
SINGLE MECHANISMS UNDERPINNING
YOUR PATH STATES AND WE WANT TO
DISCOVER SAFE AND EFFICACIOUS
NONOPIOID BASED THERAPY.
EVERY DISCOVERED BIOMARKERS THAT
WOULD ALLOW US TO CATEGORIZE THE
PATIENTS SO AS TO PROVIDE
PERSONALIZE TREATMENT AND THEN
WE WANT TO TRANSLATE DORPHY FROM
BENCH TO CLINICAL TRIALS.
SO AS DR. JACOBSEN SAID, WE
STARTED STUDYING THIS AND WE ARE
INTERESTED IN THE OXIDATIVE
STRESS, SO PURPOSE FOR TODAY I
WILL FOCUS ON 1 OF THE GPC Rs,
BEFORE I DO THAT, LET ME TALK
ABOUT PAIN.
THIS AFFECTS 700 MILLION PEOPLE
WORLD WIDE, I'M ATTACHED TO
NEUROPATHIC PAIN BECAUSE IT'S 1
OF THE MOST DIFFICULT PAIN
STATES TO ACTUALLY ADDRESS.
MORE OVER, AS YOU PROBABLY KNOW,
THE CURRENT MEDICATIONS DO NOT
PROVIDE ADEQUATE PAIN RELIEF AND
HAVE A VARIETY OF SIDE EFFECTS,
SO THIS IS A SLIDE THAT WAS
PUBLISHED BY BANNISTER IN 2020,
IT WAS NOT MUCH TO UPDATE IN THE
LAST 5 YEARS AND AS CAN YOU
PROBABLY SEE IT IS A VERY SLAD
SLIDE BECAUSE IT SHOWS YOU AND
YOUR YOUR ANTIDEPRESSANTS.
WE KNOW THE PROBLEM THAT OPIOIDS
HAVE DONE IN PAIN IN GENERAL BAH
ALSO IN NEUROPATHIC PAIN BECAUSE
WHEN YOU LOOK AT THE USE OF
OPIOIDS IN 92URE O PATHIC PAIN,
YOU WILL SEE THAT A GREAT
PROPORTION OF PATIENTS THAT EVEN
THOUGH MILD TO MODERATE PAIN
SETTINGS, THEY ARE PRESCRIBED A
LOT OF OPIOID, SO IT'S BEEN A
BIG PROBLEM.
WHAT WE DO KNOW THOUGH IS THAT
FOR THE MOST PART THESE CURRENT
DRUGS THAT WE USE AFFECTS MAINLY
NEURONS, OKAY?
HOWEVER, WE KNOW FROM THE LAST
10 YEARS OR SO THAT NONNEURONAL
CELLS CONTRIBUTE TO CENTRAL
DESENSITIZATION BY ENGAGING
NEURAL INFLAMMATION IN THE
CENTRAL NERVOUS SYSTEM.
SO WE KNOW FOR EXAMPLE, CELLS
THAT ARE IN THE CENTRAL NERVOUS
SYSTEM, FOR EXAMPLE IN THE
SPINAL CORD AND MICROGLIAL CELLS
REGULATE NEURONAL EXCITABILITY
BY THE RELEASE OF SEVERAL
SUBSTANCES, SOME OF THEM CAN BE
CYTOKINES SUCH AS FOR EXAMPLE,
IL1 BETA XI WILL TALK TO YOU
MORE ABOUT IL1 BETA BUT IT CAN
INCREASE NEURONAL EXCITABILITY
BI FOR EXAMPLE, ACTIVATING ERK,
WHICH INTURN CAN AFFECT THE
ACTIVITY OF THE NMDA RECEPTORS
AND SO THIS WILL THEN RESPOND
MORE AGGRESSIVELY FOR EXAMPLE,
SYNAPTIC NEURAL TRANSMISSION.
AT THE SAME TIME THIS KIND OF
CELLS CAN ALSO RELEASE E ACTIVE
OXYGEN SPECIES WHICH CAN NITRATE
AND DEACTIVATE ASTRO CITE
TRANSPORTERS TO HAVE SYNAPSE
WITH THE MORE GLUTAMATE PRESENT
IN THE SYNAPSE AND INCREASED
NEURONAL EXCITABILITY.
AT THE SAME TIME THESE CELLS ARE
ACTIVATED, AS A PROTECTIVE
MECHANISM THEY WILL RELEASE
NEUROPROTECTIVE MOLECULES AND I
AM SHOWING YOU HERE WOON THAT WE
ARE REALLY EXCITED AND REALLY
LIKE IS IRPT LUKEIN 10, SO
INTERLEUKIN 10 IS FIEWR O
PROTECTIVE AND INHIBITS
NEURONONAL EXCITABILITY.
SO THE CELLS ARE EXCITED, THEY
RELEASE A LOT OF PROINFLAMMATORY
CYTOKINES BUT THEY ALSO RELEASE
ANTIBIN FLAMMATORY CYTOKINES TO
TRY TO DAMPEN THE EXTENT OF THE
PROCESS EMPLOY WE ALSO KNOW IN
PRESPONSE TO NERVE YOUR OR CHEMO
THERAPY FOR EXAMPLE, YOU HAVE
INFILTRATING, IT CELLS IN THE
CENTRAL NERVOUS SYSTEM THAT CAN
ALSO INCREASE AND NEURONAL
EXCITABILITY, SO TO MAKE A LONG
STORY SHORT, WHAT WE KNOW NOW IS
THAT NO NEURONAL CELLS HAVE MANY
RECEPTORS THAT RESPONDS TO
MEDIATORS, RELEASED IN RESPONSE
TO NOXIOUS STIMULI BY LOCALLY
ACTIVATED NEURONS ARE ALSO FOUND
WITHIN THE CIRCULATION, TAKE
EXAMPLE OF THE USE OF CHEMO
THERAPY FOR EXAMPLE, CHEEM OR
THERAPY RELEASES CYTOKINES IN
THE CIRCULATION, THESE CYTOKINES
ACCESS THE CENTRAL NERVOUS
SYSTEM WHERE THEY CAN THEN
ACTIVATE DIRECT NEURONS OR TURN
ON THESE NONIMMUNE CELLS, SO IN
ESSENCE THESE NONNEURONAL CELLS
ACCELERATE THE PAIN SYSTEM TO AN
ENDLESS INFLMA ARE TOY LOOP THAT
PROVOKES NERVES INTO GENERATING
A PERPETUAL PAIN ALARM.
SO SOMETHING THAT WE'VE BEEN
ASKING OURSELVES IS, CAN WE
TREAT THE NEUROPATHIC PAIN BY
COUNTER BALANCING NEURAL
INFLAMMATION THROUGH CELL
SPECIFIC GPC Rs ACTIVATION OR
INHIBITION AND AS I SAID WE HAVE
SEVERAL PROGRAMS HERE.
AND I THINK THAT THAT WE CAN AND
THATORY THAT I WILL PROVIDE
TODAY, IS THAT WE THINK THAT WE
CAN DO THAT BY TARGETING THIS
RECEPTOR CALLED S1 PR1 ON ASTRO
SIGHTS.
OKAY?
SO FOR THOSE OF YOU THAT ARE
FAMILIAR WITH SINGLE LIPID
METABOLISM, THEY'RE VERY, VERY
COMPLICATED SPECIES TO STUDY.
SOME OF THE MOST WELL STUDIED OF
THE SINGLE LIPIDS ARE SERIES
POINTS MID AND S1 P.
SO THIS IS A SIMPLISTIC OVERVIEW
OF THE PATHWAY, SO BASICALLY
WHAT HAPPENS IS WHEN YOU HAVE A
STIMULI, YOU MAKE SERIES POINTS
MID, BY ACTIVATING THE SINGLE
MILEN PATHWAY, BY THESE OR BY
ACTIVATING THE DE NOVO PATHWAY
BY TURNING ON TRANSFER ACE WHICH
IS THE RATE LIMITING ENZYME IN
THE PRODUCTION OF SERIES POINTS
MID.
NO SERIES POINTS MID IS
CONVERTED BY SEVERAL SPHINGO
THEN IS PHOSPHORYLATED IN
KINASES, SPHINGO IN KINASE 1
INVOLVED IN INFLAMMATION TO MAKE
THE S1 P, S1 P THEN CAN ACTIVATE
5 DIFFERENT TYPES OF GPC Rs,
S1 PR1 THROUGH 5 AND THEN SIGNAL
IS TERMINATED BY S1 P BEING
DEGREATED BOO I A VARIETY OF
FOSTER
PHOSPHATASES AND LIGASES.
SO OVER THE LAST 14 YEARS AND I
DON'T HAVE TIME TO TELL YOU HOW
I ACTUALLY GOT MYSELF INTERESTED
IN THIS PATHWAY BUT IT WAS
ACTUALLY BY MISTAKE AND I'M GLAD
THAT THIS MISTAKE SPANNED OUT
BUT BASICALLY WHAT WE FOUND OVER
THE LAST 14 YEARS IS SHOWN IN
THIS SLIDE.
WHAT WE FOUND WAS THAT TRAUMATIC
NERVE INJURIES, CHEMO
THERAPEUTICS AND EVEN OPIOIDS
CAN TURN ON SINGLE METABOLISM IN
THE SYSTEM AND GENERATE S1
PWHICH CAN DRIVE NEUROPATHIN
PAIN STATES BY ACTIVATING THE
SPR1 RECEPTOR AND THIS THE IS
STORY I WILL SHOW YOU TODAY.
SO REMEMBER WHEN WE TARTED IN
2008, THERE WAS ABSOLUTELY
NOTHING KNOWN ABOUT THE ROLE OF
THIS PATHWAY IN PAIN IN GENERAL
AND SPECIFICALLY IN NEUROPATHIC
PAIN STATES SO WE HAD TO TART
FROM SCRATCH.
SO 1 OF THE FIRST THINGS WE DID
AT A TIME WAS TO SAY, OKAY, IS
THIS S1 P EXPRESSED ALONG THE
PAIN NEURAL ACCESS AND IS IT
EXPRESSING RELEVANT CELLS CROSS
LINKING THE ANSWER TO THAT
QUESTION IS YES, IT IS PRESENT
ABUNDANTLY IN THE SPINAL CORD
WITH BOTH OF RODENTS AS WELL AS
MICE, AS WELL AS IN SUPER SPINAL
SITES SUCH AS IN THE RVM,
IMPORTANTLY, THE RECEPTOR IS
EXPRESSED IN GLIAL CELLS SO
THESE NONMUTANT DISEASE CELLS,
WHERE THEY FACILITATE AND WHERE
THEY HAVE AN INFLAMMATORY
PHENOTYPE.
BUT WHAT'S REALLY, REALLY
EXCITING WAS THIS WAS HIGHLY
EXPRESSED IN THE ASTRO SIGHTS
BOTH IN HUMANS AS WELL AS IN
RODENTS, MINIMAL EXPRESSION, IN
THE NEURON, SO KNOWING THAT THE
RECEPTOR IS EXPRESSED BOTH IN
HUMANS AND IN RODENTS AT
IMPORTANT SITES, WE THEN STARTED
EXPLORING THE POTENTIAL
CONTRIBUTION OF THE SYSTEM IN
NEUROPATHIC PAIN STATES, 1 OF
THE MANY MODELS THAT WE HAVE IN
THE LAB, IS THIS MODEL, SOME OF
YOU ARE FAMILIAR, CALLED
CONSTRICTION INJURY, WHERE WE
BASICALLY LIGATE THE SCIATIC
NERVE OF A MOUSE OR RAT, WE
INFLATE THE NERVE, INFLATION
AROUND THE NURVE, THEN THEY
DEVELOP ALOE DEANIA, EXAGGERATED
RESPONSE TO STIMULI THAT IS
INNOCUOUS AND HYPER ALGEEZIA
WHICH IS AN EXAGGERATED RESPONSE
TO SOMETHING THAT IS ALREADY
NOXIOUS AND THIS IS SOME OF THE
BEHAVIORIAL PHENOTYPES THAT
PATIENTS WITH NEUROPATHIC PAIN
EXHIBIT.
SO WHAT YOU SEE HERE, IF THE
LINE GOES DOWN, THAT MEANS MORE
PAIN, OKAY?
SO WE DO THE INJURY TO -- THIS
IS A RAT, AND YOU CAN THAT ABOUT
7 DAYS AFTER THAT YOU HAVE THE
DEVELOPMENT OF SEVERE PAIN, I
JUST USE THE WORD PAIN JUST FOR
SIMPLICITY.
SO SIGNIFICANT DEVELOPMENT OF
THE PAIN RESPONSE AND THEN WHAT
WE DID WAS WE ISOLATED, WE
HARVESTED, THE DORSAL HORN OF
THE SPINAL CORD, AND ASKED WHEN
THE ENZYMES THAT ARE INVOFFED IN
THE PRODUCTION OF SERIES POINTS
MID AND S1 P ARE TURNED ON AND
ACTIVATED.
AND WHAT YOU SEE ON THE RIGHT
HAND SIDE, WE LOOK THE TRANSFER
ACE, BOTH ENZYMES ACTIVATED,
KINASE 1 ACTIVITY IS ALSO
INCREASED AND WE HAVE HERE A
SIGNIFICANT INCREASE IN S1 P
LEVEL IN THE SPINAL CORD TISSUE.
SO NOW USING A VARIETY OF
AGONIST AND ANTAGONIST, WE SAID,
OKAY, CAN WE BLOCK THIS
DEVELOPMENT OF THE PAINFUL
RESPONSE IN RESPONSE TO INJURY?
SO WE USE HERE AT A TIME 1 OF
THE OLD COMPOUNDS, THIS WAS AN
S1 PR3 ANTAGONIST HERE, AND YOU
CAN SEE THAT THE DEVELOPMENT OF
MECHANICAL ALOE DEANIA PAIN IS
NOT AFFECTED BY AN S1 P OR SPR12
ANTAGONIST, VERY MINIMUM CENTER
FOR EXCELLENCE ON AGING EVEN IF
YOU USE THE S1 PR3 ANTAGONIST,
OKAY.
ON THE OTHER HAND WHAT WE FOUND
WAS THAT IF WE USE S1 PR1
ANTAGONIST, THESE ARE A VARIETY
OF FUNCTIONAL AND COMPETITIVE
ANTAGONIST, WE HAD REMARKABLE
EFFECT.
HERE IS AN OLD COMPOUND GIVEN
INTRA FECALLY, THAT MEANS
DIRECTLY OF THE SPINAL CORD OF
RATS THAT UNDERWENT SURGERY AND
IN THIS CASE, WE GIVE THIS
COMPOUND INTERRAFECALLY, AND YOU
CAN SEE THAT THE DEVELOPMENT OF
PAIN RESPONSE IS COMPLETELY
PRESENTED.
WE USE THIS NOVARTIS COMPOUND,
IN THIS CASE WE GIVE IT INTRA
FECALLY AT TIME OF MAXIMUM PAIN
AND WE HAVE A TIME DEPENDENT
REVERSAL OF THAT PAINFUL
RESPONSE, SO WE CAN BLOCK AND WE
CAN PREVENT, WE CAN BLOCK ASK
REVERSE NEUROPATHIC PAIN STATES
AND THE EFFECT THAT WE SEE WITH
THE PHARMACOLOGICAL TOOLS CAN BE
REPLICATED BY GENETIC
MANIPULATIONS, SO THIS IS THE
RESULTS, WE BELIEVE THAT
ACTIVATION, THAT FIRST THE
SYSTEM IS ACTIVATED AND 2, IT
REACTIVATES THE RECEPTOR, IT
CAUSES PAIN AND IF WE CAN
INHIBIT, WE BELIEVE PAINFUL
RESPONSES, OKAY, SO THIS ABOUT
2009, SOME DATA I SHOWED WAS
GENERATED AFTER 2009 BUT THIS IS
WHERE I WAS IN 2009, 2010, THIS
COMES UP THIS REALLY, REALLY
NICE PAPER, WHERE THEY THEY THAT
FING OLIMOD WAS APPROVED FOR THE
TREATMENT OF MULTIPLE SCLEROSIS,
YOU CAN SEE, IT HAD REMARKABLE
SUCCESS FOR MS AND BECAUSE OF
THE SUCCESS A BUNCH OF OTHER
DRUGS HAVE BEEN APPROVED FOR THE
STREEMENT OF MULTIPLE SCLEROSIS.
IN SOME OF THEM ARE MOVING
FORWARD FOR ULRICHRATIVE COLITIS
AS WELL AS SORTING SIGNALS IA
SIS, AND WE ALSO ASKED FOR THE
COMPOUND TO THE PHARMACEUTICAL
COMPANY ANDS THEY DIDN'T GIVE IT
TO US SO WE JUST WENT THROUGH
THE PATENT AND MADE ALL OF THEM
AND TESTED THEM AND SO HAD A
LITTLE BIT OF A BUSY SLIDE, TOOK
MANY YEARS TO GENERATE, AND WHAT
YOU SEE IS THAT DIFFERENT
FUNCTIONAL ANTAGONIST THAT THIS
IS YOUR PAIN RESPONSE AFTER
NERVE INJURY.
WE GIVE IT SPINOMID MORE THAN
ANY OTHER DRUGS AND IN EVERY
SINGLE COMPOUND WE HAVE A VERSAL
THAT ESTABLISHED MECHANICAL ALOE
DEANIA, AND WE DID A LOT OF
STUDIES USING BEHAVIOR, WE
DEMONSTRATED THAT WE HAD
CONDITIONAL PLACE PREFERENCE
ONLY IN INJURED ANIMAL.
WE'VE SHOWN THE EFFECT OF THE
NALOXONE INDEPENDENT, SUGGESTING
THEY'RE NOT ENGAGING AN OPIOID
SYSTEM, AND WE ALSO FOUND NOR
SEX DIFFERENCES ON THE
BEHAVIORIAL PHENOTYPE OR THE
DRUG RESPONSE.
NOW I WILL GIVE YOU 1 EXAMPLE, I
SAID THESE DRUGS ARE FUNCTIONAL
ANTAGONIST AND YOU KNOW WHAT
THAT MEANS, YOU KNOW THIS IS IN
THE CASE OF FTY, FTY NEEDS TO BE
PHOSPHORYLATED FTY AND THEN
BASIC LE, INITIALLY ACTIVATE THE
RECEPTOR AND INTERNALIZED AND
THEN CAUSE A PERMANENT
DEGRADATION OF THE RECEPTOR SO
THERE IS NO SIGNALING OF SPR1 AT
THE CELL SURFACE MEMBRANE, SO
THEY'RE ALL FROM ANTAGONIST, SO
1 OF THE THINGS WE HAD TO
ESTABLISH WAS WE ACTUALLY
LOOKING HERE AT THE S1 P S1 PR1,
ANTAGONISM AND WE DID A LOT OF
TIME AND EXPERIMENTS AND THIS IS
JUST 1 EXPERIMENT I WILL SHOW
YOU.
WE USED THIS HIGHLY SELECTIVE S1
PR1 ANTAGONISM AND DOES IT CAUSE
OR INHIBIT PAIN.
EVERYTHING WE TRIED WITH THIS
HIGHLY CONNECTED AGONIST, THEY
CAUSE SEVERE PAIN, SO WE
EXCLUDED SPR 1 AS A MECHANISM OF
ACTION, AND WE SUBSTANTIATED
THAT BY LOOKING AT A VARIETY OF
COMPETITIVE ANTAGONIST SHOWN ON
THIS SLIDE FOR EXAMPLE, THIS IS
2 COMPOUNDS THAT ARE PURE
ANTAGONIST AND BEHAVE EXACTLY
LIKE THE FUNCTIONAL ANTAGONIST,
BEAUTIFUL REVERSAL OF THAT
RESPONSE.
AND THIS IS JUST A SLIDE THAT
SHOWS SOME OF THE COMPOUNDS THAT
WE'VE TESTED, ALL OF THEM ARE
SELECTED FOR S1 PR1, AND YOU
NOTE THAT SOME OF THE LATER
GENERATIONS SUCH AS OZANIMOD,
THEY DON'T ACT AS THE RECEPTOR
BECAUSE IT WAS THOUGHT THAT WITH
THE CARDIA WITH THE FUNCTIONAL
SP1 R1 ANTAGONIST WAS DUE TO
ACTIVATION OF S1 PR3, SO ALL
PHARMACEUTICAL COMPANIES HAVE
ENGINEERED OUT SPR13 FROM THE
MOLECULE BUT IT TURNS OUT THE
SIDE EFFECT IS MEDIATED BY
ACTIVATION OF S1 PR1.
WE NEXT WANTED TO KNOW WHETHER
THESE COMPOUNDS HAD THE
POTENTIAL TO CAUSE ANALGESIC
TOLERANCE SO HAD IS A SIMPLE
EXPERIMENT DONE WITH A 6 DAY
MINIPUMP EMPLOY WE TAKE THE RAT,
CAUSE NERVE INJURY, PUT THESE
MINIPUMP SUBCUTANEOUSLY AND
DELIVER THE DRUGS SUBCUTANEOUSLY
AND YOU CAN SEE THAT AS WE START
INFUSING, THERE IS REVERSAL OF
THE PAIN RESPONSE WHICH
BASICALLY LASTS UNTIL THE PUMP
DELIVERS THAT DRUG.
IF I WERE TO DO THIS WITH
MORPHINE AFTER 1 DAY, I WOULD
LOSE THE ACTION AND WE'VE
ACTUALLY GONE FURTHER OUT TO 14
DAYS MINIPUMPS AND THEN
EXPERIMENTS BECOME TOO
EXPENSIVE.
ANOTHER QUESTION WE NEEDED TO
ESTABLISH WAS, OKAY, HOW DO
THESE DRUGS COMPARE WITH WHAT IS
USED IN THE CLINIC NOW.
SO THIS A LITTLE BIT COMPLICATED
BUT FOR THE PHARMACOLOGIST WE
WILL GET IT.
SO WHAT WE HAVE HERE ON THE
Y-AXIS IS THE REVERSAL OF PAIN,
AT TIME OF PEAK REVERSAL OF THE
DRUG.
AND WE'VE USED 3 COMMONLY USED
ANALGESIC MORPHIN, GABBA PENTINE
REGIMENIN AND AMTRIP LINE WITH
80/50 OF 8 MICROMOLES FOR AMTRIP
LINE AND 40 FOR GABBA PENTINE
REGIMENIN, BUT IF YOU NOTICE
THEY LOOK AT THE SHIFT TO THE
LEFT IN POTENCY AND EFFICACY OF
THESE COMPOUNDS.
TOTAL SHIFT TO THE LEFT AND WHEN
YOU CAM PAIR THE 50S, YOU CAN
SEE THERE ARE VERY POTENT DRUGS.
MORE OVER WHAT WE DISCOVERIED
WAS THAT THESE COMPOUNDS CAN
ALSO BE GIVEN AS ADJUNCT TO
OPIOIDS AND THIS IS VERY COOL
STORY THAT WAS FUNDED BY NIH
NIDA SEVERAL YEARS AGO MUCH SO
THIS A TYPICAL EXPERIMENT YOU
CAN LOOK FOR THE DEVELOPMENT OF
TOLERANCE, YOU MAKE YOUR INJURY,
THIS IS THE PAIN THAT HAPPENS
AND THEN YOU GIVE IT DAILY,
DAILY INYEKS OF MORPHINE.
AND YOU CAN SEE FIRST DOSE,
BEAUTIFUL REVERSAL, SECOND DOSE,
THIRD DOSE AND OFF YOU GO AND
YOU COME HERE AFTER ABOUT 7, 6
DOSES, MORPHINE LOSES IT'S
ANALGESIC ACTION AND THIS IS A
TOLERANCE.
WELL, WE THEN DEMONSTRATED WAS
THAT IF YOU TAKE MORPHINE AND
YOU COMBINE IT WITH A VERY LOW
DOSE OF AN SPR1 ANTAGONIST, @
DOSE THAT OUR SUBANALGESIC THAT
CAUSES 5 PERCENT ANNAL GEEZIA
WHEN GIVEN ALOAP, WE BEING
COMPLETELY PROTECT THE LOSS OF
ANALGESIC ACTION TO MORPHINE.
LET'S LOOK AT THE LAST DAY HERE.
THIS A TOTAL LOSS OF MORPHINE
ANALGESIC ACTION AND THIS IS THE
RESPONSE OF MORPHINE WHEN
COMBINED TO 2 OF THE FUNCTIONAL
-- TO S1 PR1 ANTAGONIST.
SO WE BELIEVE THAT THESE ARE S1
PR1 AN TAB TAGANIST, WE
PRESENTED SEVERAL PUBLICATION
HERE.
WE UNDERSTAND MECHANISM OF
ACTION.
I DON'T HAVE TIME TO DELVE INTO
THAT BUT SUFFICE TO SAY, THAT
IT'S A VERY, VERY INTERESTING
STORIES THAT COULD BE PURSUED IN
GOING FORWARD BECAUSE I DON'T
THINK THAT YOU WILL HAVE 1 DRUG
THAT CAN BE EFFECTIVE FOR ALL OF
THE PATIENTS AND SO THE ABILITY
TO DO COMBINATION PHARMACOLOGY
WILL BE VERY IMPORTANT.
JUST TO SAY THAT THE S1 PR1
SYSTEM HAS NO ROLE IN NORMAL
PAIN TRANSMISSION AND THIS IS A
TYPICAL TEST THAT WE DO, I THINK
THIS IS A TAIL FLICK OR HOT
PLATE AND THIS IS THE RESPONSE
TO MORPHINE, SO YOU CAN SEE WE
HAVE A PAIN RELIEF IN THIS TEST
AND THESE DRUGS, THE S1 PR1
ANTAGONIST HAVE NO ACTUAL
RESULT.
THIS IS GOOD BECAUSE PAIN IS
PROTECTIVE AND WE DON'T WANT TO
INTERFERE WITH NORMAL PAIN
SIGNALING, SO THE NEXT QUESTION
WAS, CAN YOU DIRECT ACTIVATION
OF THE S1 PR1 RECEPTOR
RECAPITULATE THE BEHAVIORIAL
PENE PHENOTYPES THAT ARE
ASSOCIATE WIDE NEUROPATHIC PAIN.
SO WE DID THE VERY SIMPLE
SPRPTS, WE USE AGONIST THAT I
MENTIONED TO YOU EARLY, EARLY
ON, WE GAVE IT SPINEALLY, AND
YOU CAN SEE HERE THAT A SINGLE
ADMINISTRATION OF AN SPR1
AGONIST CAUSES SEVERE MECHANICAL
ALLODEANIA, WHICH IS BLOCKED BY
S1 PR1 ANTAGONIST.
SO WE HAD NO IDEA TO POTENTIAL
MECHANISMS WHEREBY ACTIVATION OF
SP1 COULD CAUSE PAIN.
BUT IN THOSE DAYS THERE WAS A
LOT OF DATA THAT WAS COMING OUT
FROM THE FIELD SUGGESTING AN
IMPORTANT ROLE OF TRANSCRIPTION
FACTORS AND MAP KINASES IN
VARIOUS CHRONIC PAIN SETTINGS,
SO WE FELT THAT IT WAS GOOD
STARTING POINT FOR US TO
INVESTIGATE, SO WE'VE LOOKED AT
2 PATHWAYS.
WE LOOKED AT THIS READ SENSITIVE
TRANSCRIPTION FACTOR CALLED
NF-KAPPAB, AS WELL AS MAP KINASE
CALLED P38 AND AT BOTH CASES AT
TIME OF PEAK PAIN WE AWE A
SIGNATURES MIF KABT INCREASE IN
ACTIVATION OF THE NF-KAPPAB
SYSTEM AND ALSO THE MAP KEEN
ACE.
SO THESE DAYS WERE EXCITING
BECAUSE WE KIND OF THEN NEW AND
THIS IS A PROGRESSIVE STORY SO
THIS IS A STORY DURING THE
YEARS, AFTER A COUPLE OF YEARS,
THERE WAS INFORMATION COMING UP
THAT SUGGESTED THAT BOTH P38 AND
NF CAPPA B WERE VERY IMPORTANT
IN ACTIVATION OF THE
INFLAMMASOME, THE NLRP3, AND
NLRP3 AND VERY EXCITING BECAUSE
IT IS THE ENZYME THAT BASIC LE
ACTIVATE CASPACE 1 WHICH CLEANS
AND CONVERTS TO MAKE IL1 BETA.
AND AS I MENTIONED BEFORE
ILBETTA IS A NEW INSIGHTATTORY
CYTOKINE SO I LIKE TO GO AFTER
THIS PROTENTIAL PATHWAY AS A
PROPOSED MODEL.
AND SO WE LOOK AT THE ACTIVATION
OF FINAL AP3 AND AS YOU CAN SEE
ON THE BOTTOM, THE SYSTEM WAS
TURNED ON.
WE SAW AN INCREASE HERE AND
EXPRESSION OF NLRP3, ACTIVATION
OF CASPACE 1 AND INCREASED
PRODUCTION OF IL1 BETA AND SUCH
ACTIVATION WAS BLOCKED BY AT S1
PR1 ANTAGONIST.
SO WE BELIEVE THAT THIS IS
WOPOTENTIAL MECHANISM WHEREBY S1
PR1 INVOLVES PAIN.
SO NOW WE HAVE TO BACK TRACK AND
SAY IS THIS MECHANISM ALSO
INVOLVED IN THE ACTUAL
NEUROPATHIC PAIN STATES SO WE
WENT BACK TO OUR ANIMAL MODEL OF
TRAUMATIC NERVE YOUR AND WHAT WE
DID WAS TO ACTUALLY REMOVE THE
DORSAL HORN OF THE SPINAL CORD 1
HOUR AFTER TREATMENT AND PROCEED
FOR SOME OF THIS PATHWAY AND I
WANT TO SHOW YOU HERE WHAT WE
FOUND AND THIS IS ONLY JUST A
COUPLE OF DATA POINT, THE REST
OF IT IS ALL PUBLISHED AND WHAT
WE FOUND IS THAT IL1 BETA IS
ACTUALLY INCREASED IN RESPONSE
TO TRAUMATIC NERVE INJURY, THAL
HAS ACTUALLY BEEN SHOWN BY MANY
OTHERS BUT WHAT WAS VERY
EXCITING WAS THAT THIS WAS
BLOCKED WHEN WE BLOCKED S1 PR1
EMPLOY BUT WAWE FOUND, WHAT WE
SAW WAS AS IL1 BETA WAS
INCREASED AND WE LOOKED AT IL10,
AS I SAID, IT'S VERY POTENT
INFLAMMATORY CYTOKINE.
SOMETIMES WE FOUND THAT THERE
WAS A SLIGHT INCREASE, SOMETIMES
A SMALL, NO CHANGE, BUT THE REAL
EXCITING PORTION WAS RIGHT HERE;
WAS THIS DRAMATIC INCREASE IN
IL10 PRODUCTION AND SO, WE HAD
NO IDEA WHETHER THIS WAS A FLUKE
THAT TIMES, YOU KNOW CYTOKINES
GO UP AND DOWN ASK THEY HAVE NO
PHARMACOLOGICAL MEANING
WHATSOEVER, AND SO WE WANT TO IS
THIS INCREASE IN IL10
MEANINGFUL, DOES IT CONTRIBUTE
TO THE MODE OF ACTION OF SP1AN
TAGANIST AND TO DO THIS WE'VE
DONE THIS EXPERIMENT.
IT'S A BIT COMPLICATED BUT ALSO
KIND OF EASY.
SO THIS IS A RAT AND WE CAUSE
INJURY, 7 DAYS AFTER WE GO AND
IMPLANT THIS MINIPUMP THAT WILL
DELIVER EITHER NIBR15 OR FTY720.
AND AS I MENTIONED BEFORE THE
UMP YOU PUMPS ARE DELIVERING AND
YOU HAVE THE PAIN RELIEF THAT
LAUGHS UNTIL THE PUMP STOPS
PUMPING AND SO WHAT WE SAID WAS,
IF THIS ANALGESIC ACTION IS
MEDIATED BY THIS INCREASE IN
IL10, WE SHOULD BE TO BLOCK THE
ANALGESIC ACTION AND REVERT IT
BACK TOAIN IF WE TAKE IL10 OUT
FROM THE EQUATION, SO THIS IS
EXACTLY WHAT WE DID, WE GAVE IT
AN INTRA FECAL ADMINISTRATION OF
AN EABT BODY AGAINST IL10 AND
WHAT YOU SEE HAPPENING IS RIGHT
HERE.
THE ANTIBODY WE USE ANALGESIC
ACTION AND YOU CAN DO IT AGAIN
AND AGAIN.
AND THEN WE'VE ALSO USE A IL10
KNOCK OUT ANIMAL, THIS IS THE
RESPONSE OF THE 2 DRUGS, 2
SPR1AN TAGANIST, REVERSAL OF THE
PAIN PAIN RESPONSE AND COMPLETE
LOSS OF THE ANALGESIC ACTION IN
THE KNOCK OUT ANIMAL.
SO WE BELIEVE THAT IL10 IS ALSO
CRITICAL OF THE MECHANISM OF
ACTION OF THESE DRUGS.
SO IF WE MOVE, IF WE WANT TO
CONSIDER S1 PR1 AS A POTENTIAL
TARGET FOR DIFFERENT TYPES OF
NEUROPATHIC PAIN, YOU HAVE TO
TEST THE MOLECULES AND THE
HYPOTHESIS, IN A VARIETY OF
SETTINGS SO THAT YOU CAN THEN --
SO THAT HOPEFULLY YOU CAN THEN
CHOOSE WHAT THE BEST CLINICAL
POPULATION IS GOING TO BE AND 1
OF THE RESEARCH AREA, IN MY
LABORATORY THAT IS VERY, VERY
INTERESTED IN, IS CHEMO THERAPY
INDUCED NEUROPATHIC PAIN, SO
CHEMO THERAPY INDUCED PAIN IS 1
OF THE TOXICITIES OF WIDELY USED
THERAPEUTICS THAT HAVE
DRASTICALLY DIFFERENT MECHANISM,
IT HAPPENS WITH THE DRUGS, WITH
PLATINUM BASED DRUGS, VINCA
ALKALOIDS, PROTEIN COMPLEXIOSOME
INHIBITORS AND OTHER NEW
BIOLOGICS.
IT IMPACTS THE TREATMENT OF
CANCER PATES BUT IT ALSO HAS A
MAJOR IMPACT FOR THE QUALITY OF
LIFE FOR THE CANCER SURVIVORS.
AND BY 2040 WE'RE EXPECTING
26 MILLION CANCER SURVIVORS SO
ADDRESSING THIS IS OF MAJOR
IMPORTANCE AND THERE ARE NO
APPROVED DRUGS.
SO, AS I SAID, WE'VE SPENT MANY
YEARS LOOKING AT CIPN, WE HAVE
ALL OF THE ANIMAL MODELS IN THE
LAB AND I WILL JUST GIVE YOU A
LITTLE EXAMPLE OF SOME OF THE
ROLE OF S1 P THAT IS VERY
CONSISTENT TO WHAT WE ALSO SEE
IN TRAUMATIC NERVE INJURY
MODELS.
SO THIS IS AN EXAMPLE OF P A
CLITAXEL, WIDELY USED FOR BREAST
CANCER, WE USE IT IN RATS, WELL
DEFINED DOSE IN NAIVE ANIMALS
AND WE CAN TALK ABOUT TUMOR
BEARING ANIMALS LATER.
BUT WHAT YOU SEE IS THAT AFTER
THE FIRST ROUND OF P A CLITAXEL,
IF YOU MONITOR THE DEVELOPMENT
OF PAIN, METRICS MECHANICAL ALOE
DEANIA, YOU HAVE SIGNIFICANT
DEVELOP AM OF THAT ALOE DEANIC
RESPONSE.
ON SO THIS IS PROBABLY WHAT IT
LOOKS LIKE WHEN THE PATIENT
RECEIVES THESE DRUGS AND THEY
PUT THE SHIRT ON, JUST THE TOUCH
ON THE SKIN CAUSES PAIN SO THIS
IS DEFINED AS ALOE DEANIA.
SO WE REMOVE HERE THE DORSAL
PART OF THE SPINAL CORD AND WE
PROBE FOR THE ACTIVATION OF
THESE ENZYMES AND AS I SHOWED
YOU BEFORE -- SERIES POINTS MID
IS 1 OF THE MOST POTENT PRO
APOPTOTIC MEDIATOR.
TURNS OUT THAT S1 P IS A VERY
APPROPRIATE MEDIATOR SO THIS I
DIDN'T THINK AND YANG OF SERIES
POINTS MID IN S1 P, SO IN FACT
PEOPLE ARE GOING AFTER S1 P, AND
IN THE S1 P ARE RECEPTOR AS A
NOVEL ANTICANCER TYPE OF
APPROACH.
SO THE SYSTEM IS TURNED ON, IN
THESE MODELS AND CONSISTENT TO
OTHER MODELS OF TRAUMATIC NERVE
INJURY, CHEMO THERAPEUTICS
ACTIVATE REDOX SENSITIVE
TRANSCRIPTION FACTORS AND MAP
KINASES, AND HERE I SHOW
NF-KAPPAB AND P65, HERE I GIVE
YOU AN EXAMPLE OF ERK WHICH IS
ANOTHER MAP KINASE AND IT'S
INCREASED AND ACTIVATION OF P38
AND WE KNOW THAT THESE SIGNALING
PATHWAYS ARE PHARMAICOLOGICALLY
IMPORTANT BECAUSE IF WE BLOCK
THEM WE CAN ALSO PREVENT
DEVELOPMENT OF ALLODYNIA SO THEY
ARE MEANINGFUL.
OKAY, SO THIS IS ACTUALLY --
THIS PAPER WAS PUBLISHED IN
2014, THIS EXPERIMENT WAS
ACTUALLY GENERATED IN 2010.
SO ABOUT 4 YEARS TO WRAP OUR
HEAD AROUND ALL OF THIS.
THIS WAS 1 OF THE VERY OLD FIRST
COMPETITIVE S1 PR1 ANTAGONIST
CALLED W146, IT'S A DIRTY
COMPOUND, WE DIDN'T KNOW HOW
LONG TO TREAT THE ANIMALS FOR SO
WE DECIDED WE WOULD TREAT FOR 16
DAYS.
THE COMPOUNDS WERE GIVEN INTRA
FECALLY AND YOU CAN SEE HERE
THAT BASICALLY IF WE BLOCK S1
PR1, WE PREVENT THE BIRTH OF
ALEE DEAN RAW DATA AND HYPER
ANNAL GEEZIA IN A DOZE DEPENDENT
MANNER AND MECHANISM BY WHICH
THIS HAPPENS AS I MENTION IN THE
PREVIOUS MODEL IS BY BLOCKING
NF-KAPPAB.
AS YOU SEE WE PLOK IT AND MAP
KINASES AND WHEN WE LOOK AT
CYTOKEENS AGAIN AND CONSISTENTLY
WE ALSO BLOCK AND ATTENUATE
THESE PROINFLAMM -ATORY BETA,
IL10 AND WHEN WE LOOK AT IL10 IS
INCREASES, THIS IS INCREASINGLY
RESULTS, IL4 IS INCREASED WE
HAVEN'T DONE EXPERIMENTS THAT
WE'VE DONE FOR IL10 BUT IN THE
FUTURE, IT COULD BE SOMETHING
INTERESTING TO PURSUE.
SO MORE RECENTLY, WE SAID, OKAY,
WHAT HAPPENS IF WE GIVE THE DRUG
ONLY, SO WE HAVE THE NEWER DRUGS
THAT CAME TO MARKET, SO WE
SCREEN THEM AND WE SAID CAN WE
BLOCK THE DEVELOPMENT OF
NEUROPATHIC PAIN BY GIVING AND
RESTRICTING THE USE OF THESE
ANTAGONIST ONLY WHEN THE RAT
SEES THE CHEMO THERAPEUTICS.
BECAUSE WHEN YOU LOOK AT THESE
PAINFUL ASSOCIATION WITH
NEUROPATHIC PAIN, IT'S PROBABLY
THE ONLY ASSOCIATION WHERE YOU
CAN GO IN AND GIVE THAT DRUG
WHEN THE PATIENT SEES THE CHEMO
THERAPEUTIC, ALL THE OTHER
INSTANCES YOU WANT DRUGS THAT
WORK THERAPEUTICALLY BUT HERE WE
HAVE THE OPTION OF WORKING
PROPHYLACTICALLY AS WELL AS
THERAPEUTICALLY AND THIS WAS
REALLY ASTONISHING, ONLY WHEN WE
RESTRICTED THE CHEEM OR
THERAPEUTIC WITH -- CHEMO
THERAPEUTIC WITH THE SP1 R1 AN
TANANIST, COMPLETELY PREVENTED
THE DEVELOPMENT OF NEUROPATHIC
PAIN.
SO THE MECHANISM UNDERLYING THIS
DISEASE PHENOTYPE BUT DON'T
UNDERSTAND BUT WE HAVE REALLY
EXCITING DATA FROM THE SINGLE
CELL RNASEQ DATA AND WE
SUBMITTED THE PAPER YESTERDAY TO
PAIN AND I DON'T HAVE TIME TO --
WE CAN TALK LATER ABOUT THAT.
WE'VE TESTED MANY COMPOUNDS,
WE'VE OBTAINED SIMILAR
EXPERIMENTS, RESULTS WITHOUT THE
CHEMO THERAPEUTICS AND
EXPERIMENTS IN TUMOR BEARS MICE
ARE ONGOING IN PROGRESS.
I CAN JUST TELL YOU THAT THE
DRUG WORKS IN TUMOR BEARING MICE
THAT ALSO PREVENT THE TUMOR
GROWTH AS SHOWN BY OTHERS, AND
THE PRESENCE OF THE TUMOR ITSELF
DOES NOT MAKE THE PAINFUL
PHENOTYPE WORSE.
BUT THERE'S A VERY COMPLICATED
EXPERIMENTS, IN WORKING WITH 1
YEAR AND WE STILL ARE NOT DONE
WITH IT, BUT WE ARE DOING --
WE'RE MAKING PROGRESS, SO, THEY
NOT ONLY CAN BLOCK IT BUT THEY
CAN ALSO PREVENT IT, THIS IS AN
EXPERIMENT DONE ON DAY 16 WHEN
YOU HAVE MAXIMUM PAIN WE FUSE IN
THE LIVER 3 DIFFERENT KIND OF
COMPOUNDS SHOWN HERE AND IN ALL
INSTANCES WE CAN REVERSE THAT
PAINFUL PHENOTYPE.
THIS IS BEAUTIFUL BUT IF YOU CAN
JUST LOOK AT THE ACTIVATION OF
THESE, ALL OF THESE PATHWAYS AND
ALL THESE SPHINGOLIPIDS THEY ARE
INCREASED IN RESPONSE TO SIMPLE
CHEEM OR THERAPEUTIC.
AS I MENTIONED WHAT IS EXCITING
HERE IS THAT THE S1 PR1
ANTAGONIST ARE MOVING FORWARD AS
ANTICANCER DRUGS SO WE MAY HAVE
AN OPPORTUNITY WHERE WE MIGHT
PREVENT NEUROTOXICITY AND ALSO
ADDRESS THE TUMOR BURDEN ITSELF.
ALL RIGHT, SO THEN NEXT QUESTION
WAS, WHAT IS THE CELLULAR
SUBSTRATE FOR SP1 R1 ACTIVITY?
SO YOU REMEMBER AT THE BEGINNING
THAT SP1 R1 IS HIGHLY EXPRESSED
ON THE ASTROCYTES IN HUMANS AND
IN RODENTS BUT ALSO IT'S
DRASTICALLY INCREASED IN THE
ASTRO SITTIC POPULATION.
WE FOUND THAT IN MODELS OF
NEUROPATHIC PAIN BUT A LOT OF
THIS DATA WAS ACTUALLY -- WAS
ACTUALLY GATHERED AT A TIME BY
WONDERFUL WORK BY GERALD SHUN
CHOI AT THE SCIPTSWHERE HE
SHOWED THAT ASTRO SIGHTS ARE
AFFECTED BY THESE SP1 R1
ANTAGONIST AND THEY CONTRIBUTE
TO THE DEVELOPMENT OF MULTIPLE
SCLEROSIS.
SO PUTTING HIS DATA TOGETHER AND
OUR DATA TOGETHER, WE STARTED A
COLLABORATION AND SAID, WELL,
YOU KNOW, IF THAT'S THE
MECHANISM OF ACTION IN MULTIPLE
SCLEROSIS AND S1 PR1 IS IN THE
ASTRO SIGHT MAYBE WE SHOULD HAVE
SIMILAR EFFECT.
THIS WAS OUR HYPOTHESIS.
WE COLLABORATED AND HE SENT US
HIS MICE AND SO WHAT YOU SEE
HERE AND ALL OF THIS DATA IS
PUBLISHED SO THIS IS OUR ASTRO
SIGHTIC SPECIFIC SPR1 KNOCKOUT
MICE.
WE'VE DONE MANY, MANY TESTS AND
THE BOTTOM LINE IS I DID NOT
DEVELOP ALLODYNIA IN RESPONSE TO
S1 PR1 ACTIVATION, THIS IS THE
WILD-TYPE, THIS IS WHERE WE GIVE
INTRA FECAL ADMINISTRATION OF
THE WILD-TYPE, NOTHING HAPPENS
IN THE KNOCK OUT, THIS IS A
MODEL OF TRAUMATIC NERVE INJURY,
THIS IS THE RESPONSE IN THE
WILD-TYPE, YOU HAVE THE PAINFUL
RESPONSE, NOTHING HAPPENS IN A
KNOCK OUT AND THIS IS WITH THE
DISEASE IN THE WILD-TYPE AND
THIS IS THE KNOCK OUT.
ALL OF IT IS PUBLISHED, OKAY, SO
WHEN WE LOOK AT THE RESULTS,
THEN IN THE ASTRO SIGHT SPECIFIC
KNOCK DOWN MICE, WE FOUND WHAT
HE ALSO HAS FOUND IN THE MODELS
OF THE MULTIPLE SCLEROSIS AND
THAT IS THAT WE LOSE THE
PHARMAICOLOGICAL ACTION OF THESE
DRUGS.
SOPHISTICATEDY THIS IS AN
EXAMPLE IN THE TRAUMATIC NERVE
INJURY, AND THIS IS BORTEZOMIB,
SAME THING IN THE BORTEZOMIB, SO
WE BELIEVE THIS WAS PUBLISHED
AND ASTRO SIGHTS CONTRIBUTE TO
SP1 R1 NEUROPATHIC PAIN STATES
AND THEY'RE ALSO TARGET FOR
PHARMAICOLOGICAL ACTION, AND WE
REALLY KIND OF LIKE THIS,
BECAUSE WE HAVE NOW 1 CELL TYPE
THAT CAN RESPOND TO THAT DRUG.
SO THIS IS A WORKING HYPOTHESIS
THAT WE BUILD OVER THE LAST 14
YEARS, LITTLE BY LITTLE FOR
CHEMO THERAPY INCREASES S1 P
WHICH THEN ACTIVATE THE
RECEPTOR, TURNS ON P38 AND
ACTIVATES THE INFLAMMASOME, IL1
BETA IS RELEASED, THIS IS A
SLIDE MADE VERY, VERY SIMPLE,
AND THEN IL1 BETA CAN INCREASE
NEURONAL ACCESSIBILITY BY
PRESYNAPTICALLY OR POST
SYNAPTICALLY BUT IT WAS VERY
SIMPLE BECAUSE IERK L1 BETA CAN
ACTIVATE SURROUNDING DPLEEL
CELLS AND SO FORTH BUT WE ALSO
KNOW FROM THE LITERATURE AND
WE'VE ALSO DONE EXPERIMENTS THAT
IL1 BETA BY ACTIVATING ON GLIAL
CELLS CAN ACTUALLY DAMPEN IL10.
SO THERE WAS LESS IL10 THAT WAS
RELEASED.
AS I MENTIONED THIS IS VERY
COMPLICATED AND WE KNOW IT'S NOT
ONLY ABOUT THE ASTROCYTE BECAUSE
THERE'S COMMUNICATION WITH THE
INFILTRATING T-CELLS WITH
MICROGLIA AND OTHER CYTOKINE --
OTHER DPLEEL CELLS.
SO WHEN WE BLOCK THE RECEPTOR,
WE THEN INHIBIT BASICALLY THE
INFLAMMASOME, WE REDUCE LEFT
SIDE IL1 BETA TO BE RELEASED AND
NOW IL1 BETA THE BREAK, WE TAKE
OFF THE BREAK THAT ILBETTA 1 HAS
ON IL10 AND WE HAVE MORE IL10
COMING OUT AND THEN IL10 CAN
DAMPEN NEURONAL EXCITABILITY BY
SEVERAL MECHANISM, 1 ILLUSTRATED
HERE IS BY ACTIVATING THE
RECEPTOROT PRESYNAPTIC NERVE
TERMINAL.
NEXT QUESTION, THIS IS SOMETHING
WE ARE WORKING ON HERE, OKAY, SO
WHAT TRIGGERS THE ENHANCED
PRODUCTION OF THESE SINGLE
LIPIDS.
WHAT MAKES THEM AND SO AGAIN,
FOR THIS 1, SINCE WE DIDN'T HAVE
ANYTHING TO GO WITH, WE WENT AND
LOOKED IN THE LITERATURE AND
THERE'S A LOT OF LITERATURE,
BEAUTIFUL WORK IN THE SEPSIS
FIELD AND IN COPD AND ASTHMA,
THAT WAS GENERATED OVER THE
YEARS THAT SAID THAT ILLUSTRATED
THAT THESE DAMPS OF EITHER
MEDIATORS RELEASING IN RESPONSE
TO DAMAGE, CAN ACTIVATE TLR 4,
AND THERE WAS A COUPLE OF
SEMINOLE PAPERS IN THE
LITERATURE FROM THE COPD FIELD
AND IN FACT 1 OF MY FIRST
COLLABORATOR WAS WORKING IN
COPD, AND THEY WERE FINDING THAT
ACTIVATION OF TLR4 CAN INCREASE
S1 P BY ACTIVATING THESE
ENZYMES.
SEVERAL MECHANISM IN WHICH THIS
HAPPENS.
MORE OVER, SOME ENZYME THAT
THERE ARE UPSTREAM SUCH AS
EXAMPLE, CERAMIN ACES OR SINGLE
PATHWAYS CAN BE ACTIVATED BY
REACTIVE OXYGEN SPECIES, SO WE
HAD THIS DATA FROM THE PARALLEL
FILEDS BUT IN OUR OWN FIELD, WE
KNOW AND THE TRAUMA OF CHEMO
THERAPY CAN ALSO INCREASE AND
THAT SOME MELTALS CAN BIND AND
TURN ON AND ACTIVATE TLR4 AND WE
ALSO KNOW THAT CHEMO THERAPY CAN
ACTIVATE PRODUCTION OF REACTIVE
OXYGEN SPECIES IN THE CENTRAL
NERVOUS SYSTEM AND OVER THE
YEARS I'VE SHOWN YOU NOW THE
CYTOKINES SO THIS IS JUST A
HYPOTHESIS AND WE THINK TLR4 IS
INVOLVED BUT BEFORE WE DIG INTO
-- MOVE THE HYPOTHESIS OF SIMPLE
QUESTION WAS THIS ACTIVATION OF
TLR4 IN THE SPINAL CORD CAUSES
HYPER SENSITIVITY VIA THE SINGLE
LIPID METABOLISM AND WE DID A
SIMPLE EXPERIMENT WHICH IS THE
CONANICLE ACTIVATOR THE TLR 4,
IT BINDS CAUSES RECRUITMENT OF
THE ADAPTOR PROTEINS AND ACT
VAGALL OF DOWN STREAM SIGNALING
PATHWAYS AND SO WE GAVE THAT THE
BEHAVIOR AND YOU CAN SEE HERE
THAT THE DEMONSTRATION OF
ENDOTOXIN AS SHOWN BY OTHER
CAUSES PAIN.
AND AND ASSOCIATED WITH THE
DEVELOPMENT OF PAIN WE HAVE THE
ACTIVATION OF THE ENZYME JUST AS
PEOPLE FOUND IN OTHER AREAS OF
ACTIVATION OF TLF 4 CAUSES PAIN
AND THIS IS MEIATED BY S1 P, BUT
IS THIS MEDIATED BY THE S1 P
RECEPTOR.
AND THE ANSWER TO THAT QUESTION
IS RIGHT HERE.
HAD IS THE DEVELOPMENT OF HYPER
ANNAL GEEZIA, HYPER SENSITIVITY
TO LPS AND THIS IS COMPLETELY
BLOCKED WHEN WE GIVE AN
INHIBITOR OF SPR1.
THIS IS THE CONTROL TO SHOW THAT
IN FACT, THE EFFECT OF LPS ARE
BLOCKED BY TLR4 ANTAGONIST, THIS
IS WIDELY USED TO BLOCK TLR4
PATHWAY.
SO THIS IS OUR HIPOG SIS, AND
WE'VE ACTUALLY HAD THE GRANT, WE
HAVE A GRANT NOW, THAT THAT
INVESTIGATES THE ROLE OF SINGLE
LIPID IN A NEURAL TOXICITY WHICH
IS NEURAL COGNITIVE IMPAIRMENT
AND WE'RE TEASING APART THE ROLE
OF TLR4 WHICH CELLS THE ASTRO
SIGHT, MICROGLIA THAT IS
PRODUCING THE SINGLE LIPIDS AND
SO FORTH.
SO, SO THIS IS WHERE WE ARE 14
YEARS LATER.
WE FOUND THESE ANTAGONIST HAVE
NO EFFECT ON PAIN THRESHOLD.
THEY'RE EFFECTIVE IN MANY MODELS
NEUROPATHIC PAIN IN MALES AND
FEMALES, THEY DON'T CAUSE
ANALGESIC TOLERANCE, THEY DON'T
CAUSE REWARD BEHAVIORS AND WE
PUBLISHED AND ARE OPIDDOID
SPARING, WE IDENTIFIED THAT
ASTRO SIGHTS ARE IDENTIFIED AS A
CELLULAR HUB FOR PHARMACOLOGICAL
ACTION, AND WE ALSO SAID THAT WE
USED THESE IN NEUROPATHIC PAIN
STATES.
SO SO SEVERAL YEARS AGO, THERE
WAS A MEETING AT NCI AND I
PRESENTED THE PROJECT IT AND IT
WAS -- I WAS BLESSED TO
COLLABORATE WITH CHARLES AT WAKE
FOREST HE WAS VERY MUCH
INTERESTED IN THIS PROJECT AND
WE SAID, LET'S DO APPROVED
PRINCIPLE TRIAL WHICH WAS VERY
EXPENSIVE FOR US BAH WE DIDN'T
GET THE DRUGS FROM THE CUTCHES,
SO WE HAD TO BUY IT AND THE IDEA
WAS TO DO IT AS AN ADJUNCT OF P
A CLITAXEL, TO BLOCK AND
PROTENTIALLY TREAT CIP IN WOMEN
FOR BREAST CANCER, HE FOUND A
COUPLE OF APPROVED TRIAL ANDS
THEN COVID HIT AND I THINK WE
RECRUITED LIKE 5 OR 6 PATIENTS
AND WE HAD TO STOP.
BUT NOW THAT WE HAVE BETTER
DRUGS THAN SPHINGO-AND FIND IT
NOW WITH A CLEANER MORE
SELECTIVE COMPOUNDS OF ANIMAL.
SO THIS IS WHERE WE WANT TO GO.
WHAT IS ALSO BECOMING EXCITING
IN THIS AREA IS NOW THERE ARE
MORE THERE ARE PAPERS THAT ARE
COMING OUT THAT ARE VALIDATING
WHAT WE AWE IN THE ANIMALS YEARS
AGO, SO THESE ARE VERY 2 VALID
AND RELIABLE INTERESTING PAPERS,
BOTH IN THE CIPN FIELDS WHERE
THEY ALSO SHOW SIGNIFICANT
ALTERATIONS SINGLE LIPID
METABOLISM IN CIPN.
SO 14 YEARS DOWN THE ROAD,
HERE'S WHAT WE WANT TO CONSIDER,
SOME NEUROPATHIC PAIN STATES
SHOULD BE CONSIDERED AS
SPHINGOPATHIES WHICH SHOULD BE
TREATED WITH SINGLE
SPHINGOLIPID-BASED THERAPIES.
TO THIS END I STARTED A
CONSOWRTIUM, STARTED AT THE END
LAST MONTH CONSISTING OF MYSELF
AND COLLEAGUES, IT'S A MIXTURE
OF CLINICAL PEOPLE AS WELL AS
BASIC SCIENTISTS AND OUR
THOUGHTS ARE TO REALLY START
MAKING PEOPLE AWARE OF THIS
PATHWAYS WHEN PEOPLE THINK
SPHINGOLIPIDS, THEY THINK LIPIDS
IN GENERAL, THESE ARE
SPHINGOLIPIDS AND WE WANT TO
RAISE AWARE BUSINESS SO WE WILL
PUBLISH A FIRST DEPOSITION PAPER
GOING FORWARD.
WE ALSO THINK THAT SOME OF THE
SPHINGOLIPIDS BASED ON MARCO'S
WORK CAN BE USED AS BIOMARKERS
AND I HAVE A GRANT HERE WITH
STEPHANIE AT WASH-U, TO LOOK AT
AND DO SINGEM LIPID ORDER OF
MICRONSICS AND SMALL FIBER
NEUROPATHIES.
SO WHAT IS ALSO BECOMING VERY
EXCITING IS THAT I'VE TALKED A
LOT ABOUT THE ROLE OF THE SYSTEM
RIGHT HERE IN THIS TRAUMATIC
NERVE INJURY BUT THERE'S A LOT
OF PAPERS COMING OUT IN A LOT OF
OTHER INDICATIONS, AND WHEN WE
STARTED, THERE WAS 0 PAPER ANDS
NOW YOU CAN SEE THERE ARE MANY
REHAVE YOUS ARTICLE THAT ARE
COMING OUT TAKEN--THEY REALLY
KIND OF HELP VALIDATE AND
UNDERSCORE HOW PROLIFIC THIS
FIELD IS, HOPEFULLY GOING TO
BECOME.
SO NONE OF THIS WORK WOULD HAVE
BEEN MADE POSSIBLE WITH A LOT OF
WORK FROM MY LAB, AND OTHERS
THAT HAVE DIRECTLY CONTRIBUTED
TO THIS SPECIFIC PROJECT.
MY COLLABORATORS, AS WELL AS
THOSE ASH ROUND THE WORLD THAT
HAVE JOINED US IN THIS IFORT.
A LOT OF THE INITIAL PEOPLE
HERE, YOU SEE, COLLEAGUES HERE
YOU HAVE NO INVOLVEMENT IN PAIN,
THEY JUST HELP ME WITH THE
ANALYSIS OF ALL OF THIS
INTERESTING ENZYMES THAT MAKE
SINGLE LIPIDS AND MORE RECENTLY
WE HAVE ANALYZING AND TREMENDOUS
SUPPORT FROM OUR COLLEAGUES,
EVERYBODY AT UNIVERSITY OF
ARIZONA WERE TRIEWMENTAL IN
SHOWING THE LACK OF ABUSE
POTENTIAL IN THE DRUGS IN THE
ANIMAL MODELS AND OF COURSE NONE
OF THIS WORK WILL HAPPEN WITHOUT
YOU KNOW FOUNDATIONS SUCH AS THE
MAY DAY FUND WHICH WHEN I
STARTED I COULDN'T PUT AN RO-1
TOGETHER BECAUSE IT WAS A NEW
FIELD AND IT WASN'T -- IT WAS
STILL VERY NEW EMPLOY THEY
JUCHED ON BOARD AND PROVIDED US
WITH FUNDING THAT,A LOWED US TO
PROVIDE THE IPT GREATER DATA SO
FOUNDATION VS BEEN WONDERFUL
INSTITUTIONS TO PROVOID HELP TO
INVESTIGATORS AND THE NATIONAL
IBSITUTES OF HEALTH WE HAD
FUNDING FROM NINDS, NCI AND
NIDA, THAT WITHOUT THEIR
SUPPORT, WE REALLY CANNOT
ADVANCE KNOWLEDGE AND REALLY
MAKE AN IMPACT IN HUMANS LIFE,
SO I'M REALLY, REALLY GRATEFUL
FOR THEIR SUPPORT AND I'M
GRATEFUL FOR THE INVITATION,
IT'S REALLY AN HONOR AND I'M
OPEN TO ANY QUESTION, THANK YOU.
[ APPLAUSE ]
>> HAPPY TO TAKE QUESTIONS FROM
THE ROOM, WE HAVE SEVERAL ONLINE
IF YOU WOULD LIKE TO GET STARTED
WITH 1, MAYBE START WITH 1.
OKAY.
THE S1 PR1 ANTAGONIST REDUCE
PAIN RESPONSE BUT DO THEY
REVERSE INFLAMMATION RESPONSES,
THE RECEPTORS ON THE SURFACE,
DPLEEL CELLS, DO THEY GET
INTERNALIZED AND THE ASTRO SIGHT
DESTROYED SO THERE IS NO IMMUNE
RESPONSE THAT WILL REMOVE THE
INFLAMMATORY RESPONSE AND
THEREBY CURE DISEASE?
NTHAT'S A GOOD QUESTION.
SO WE HAVE LOOKED AT -- IN THE
CANCER INDUCED NEUROPATHIC PAIN
STATES ALL OF THOSE EXPERIMENTS
WERE DONE IN A PROPHYLACTIC
MODALITY AND WE FOUND THAT YES,
WHEN WE BLOCK THE RECEPTOR, WE
CAN ATTENUATE THE INFLAMMATORY
RESPONSE, IN THE MODEL OF
TRAUMATIC NERVE INJURY, THAT
EXPERIMENTS THAT I SHOWED YOU
WITH IL1 BETA, WE FOUND THAT IN
A THERAPEUTIC MODALITY WE COULD
ALSO INHIBIT THE DEVELOPMENT OF
THE INCREASED PRODUCTION OF IL1
BETA.
SO THOSE EXPERIMENTS WERE DONE
WITH BOTH FUNCTIONAL ANTAGONISTS
WHICH WOULD CAUSE PERMANENT
DEGRADATION OF THAT RECEPTOR
RESUMABLY IN A CELL AND ASTRO
SIGHT AND ANOTHER CELL TYPE BUT
ALSO WITH THE COMPETITIVE SPR1
ANTAGONIST WHICH ARE INHIBITING
THE RECEPTOR, I DON'T KNOW IF
THAT ANSWERS THE QUESTION.
>> IT WASN'T MY QUESTION.
[LAUGHTER]
>> HEY, SO YOU'RE PROBABLY SEE
MULTIPLE POTENTIAL TARGETS EVERY
DAY THROUGH LIKE LITERATURE
REVIEWS AND RNASEQ ANALYSIS SO
YOU DO YOU EVALUATE A TARGET
POTENTIAL FOR PAIN RELIEF BEFORE
DECIDING TO CONDUCT AN
EXPERIMENT?
, OKAY, SAY THAT AGAIN.
>> YEAH, SO LIKE YOU PROBABLY
SEE A BUNCH OF TARGETS THROUGH
LITERATURE REVIEWS LIKE
POTENTIAL GPC Rs OR GENES THAT
ARE HIGHLY EXPRESSED IN CERTAIN
AREAS OR RNASEQ ANALYSIS WHERE
DIFFERENT GENES ARE UPREGULATED
HOW DO YOU PERSONALLY EVALUATE
TO EMBARK ON AN INVESTIGATION
BEFORE YOU START --
>> AH, YES, I UNDERSTAND.
I UNDERSTAND.
OKAY, SO, ON THIS PARTICULAR 1,
THE DATA WAS VERY, VERY
COMPELLING AND THE FACT THAT
THERE WERE DRUGS THAT WERE
APPROVED FOR INDICATION RAISED
MY EXCITEMENT SO THAT IS 1 THE
REASONS WHY I DECIDE TO HONE IN
ON THIS TARGET.
ANOTHER TARGET, 1 I'VE BEEN
WORKING ON WITH DR. JACOBSEN FOR
MANY YEARS WAS THE SAME REASON.
WE HAD THE TARGET IDENTIFIED IN
THE ANIMAL MODELS ISSUE THE
RECEPTOR PRESENT IN HUMAN
TISSUES AND IN RODENTS OF THE
RIGHT SITES AND THERE WERE DRUGS
THAT WERE MOVING FORWARD AS AN
ANTICANCER THERAPY FOR EXAMPLE,
THAT RAISES EXCITEMENT TO ME SO
WHEN I HAVE THAT COMBINATION,
OTHER TARGETS THAT WERE BASED ON
RECEPTOR PRESENCE IN THE HUMAN
TISSUE, HOW ROBUST THE
PHARMACOLOGY IS, VISIBILITY OF
MAKING LIGANDS AND SO FORTH.
SO WE TEASE THE PATHWAY AT
MAXIMUM AND IF THE DATA KEEPS
COMING BACK AS BEING VERY
EXCITING WE PURSUE IT, IF THE
DATA IS NOT EXCITING AFTER A
GOOD TRY, WE PUT IT ON THE SIDE.
AND WE PUT ON THE SIDE SEVERAL
PROGECS.
-- PROJECTS.
DOES THAT ANSWER THE QUESTION?
>> YES, IT DOES, THANK YOU.
>> TOUGH QUESTION COMES NOW.
>> NO, NO, THAT WAS A BEAUTIFUL
TALK.
I HAVE 2 UNRELATED QUESTIONS, 1
OF THEM, IS YOU MENTIONED THAT
THE EFFECTS OF THE DRUG THAT
THEY'RE GOOD IN BOTH MALE ANDS
FEMALES WHICH IS FANTASTIC BUT
IT WAS -- I WAS CURIOUS TO SEE,
THAT THE -- OR SURPRISED TO SEE
THAT THE MECHANISTIC PART
INVOLVED ASTRO GLUE MARIOUSA AND
TELOMERE SHORTENING LIKE
RECEPTORS WHICH ARE -- MICROGLIA
AND TOLL-LIKE RECEPTORS WHICH
ARE SEX DEPENDENT SO I WANTED TO
KNOW IF THE MECHANISTIC PART WAS
ALSO DONE IN BOTH SEXES AND IF
IT,A PLAYS TO THEM IN SAME WAY
AND YOUR THOUS ABOUT HOW IT GOES
WITH THE PRIOR LITERATURE
SHOWING SEX DIFFERENCES IN THESE
2 ASTRO SIGHTS AND TOLL-LIKE
RECEPTORS?
AND THEN THE OTHER 1 IS
UNRELATED SO I CAN GO AFTER HIM
NOKAY, SO, THAT'S A VERY GOOD
QUESTION.
ALL OF THE -- EARLY EARLY DATA
ISSUES THE 1 WHERE WE START
INDEED 2009, THAT WAS ALL DONE
IN MALES, SO ALL THE
BIOCHEMISTRY WAS DONE IN MALES
BUT THEN WE EVALUATED THE
RESPONSE OF MALES AND FEMALES TO
THE DRUG AND WE FOUND NO
DIFFERENCE WHATSOEVER IN THE
MALES AND THE FEMALES IN TERMS
OF DRUG RESPONSE.
WITH THAT SAID --
>> THE MECHANISMS --
>> SO SINCE WE DIDN'T FIND ANY
DIFFERENCE IN DRUG RESPONSE, WE
DIDN'T GO AND LOOK AT MECHANISM
BECAUSE WE MAINLY INTERESTED IN
DOES THE DRUG WORK IN THE
FEMALES AND DOES IT WORK IN THE
MALES, AND IF THE ANSWER TO THAT
WAS YES TWORKS EQUALLY EFFECTIVE
WITH EVERY SINGLE DRUG IN BOTH
MALES AND FEMALES THEN WE DIDN'T
GO AND PURSUE ANY BIOCHEMISTRY
SO I CAN'T ANSWER YOU THAT.
THERE'S OHM 1 EXAMPLE THAT WE
SAW A DIFFERENCE AND THAT WAS
WITH BOTIZAMIB, AND THAT INDUCED
PAIN IS IN FEMALE IS NOT
AFFECTED BY INTERFERING WITH
THIS PATHWAY AND WE PUBLISHED
THAT.
AND IN THAT CASE, WE DID DO THE
BIOCHEMISTRY BUT WE DIDN'T DO
SIGNAL PATHWAYS, WHATEVER, WE
WENT VERY SIMPLE BECAUSE I
DIDN'T WANT TO GET BOGGED DOWN
WITH -- SO WE JUST LOOKED AND
IT,A PEERED TO BE A DIFFERENCE
IN EXPRESSION LEVELS OF THE
RECEPTORS IN THE SPINAL CORD
MALE VERSUS FEMALE SO WE THINK
THAT MAY BE 1 EXPLANATION BUT WE
JUST PUBLISHED A PAPER BUT THAT
INFORMATION WAS VERY IMPORTANT
BECAUSE IT MEANS THAT WHEN WE GO
AND DO, AN UMBRELLA CLINICAL
TRIALS, CASE, WE WOULD NOT USE
PROTEIN COMPLEXIOSOME INHIBITORS
FOR THE BLOOD CANC EWE WOULD
JUST FOCUS ON WHAT WE HAVE THE
DAILY BASIS THEA WITH THE
PLATINUM BASED DRUGS AND THE
TAXINS.
>> GREAT.
THANK YOU.
>> OKAY.
>> THANK YOU FOR AN EXACTLIENT
TALK.
WE HAVE BEEN USING FTY720 IN OUR
LAB TO PREVENT T-CELLS FROM
LEAVING THE LYMPHNODES IS THAT
POSSIBLY PLAYING A PART IN THE
MECHANISMS YOU ARE PROPOSING
HERE?
>> I'M GLAD YOU ASKED THIS,
BECAUSE I FORGOT TO SAY THAT THE
DOSES WE USE FOR THESE DRUGS ARE
10-30 FOLD LOWER THAN THOSE THAT
ARE NEEDED TO BLOCK LYMPHOCYTE
EGRESS FROM THE LYMPHNODES.
SO, I DON'T THINK, ACTUALLY WE
PUBLISHED THAT AN IMPORTANT
MECHANISM WHEREBY THESE DRUGS
INHIBIT NEUROPATHIC PAIN STATES
BY BLOCKING THE PROGRESSION OF
LYMPHOCYTES.
>> THANK YOU.
>> I THINK IT'S MAYBE IN THE
CENTRAL NERVOUS SYSTEM AND THE
DRUG THAT I'VE SEWN BEFORE THE
S1 PR1 AGONIST, COMPLETELY
PREVENTS LYMPHOCYTE EGRESS,
FACAS FACT, WE HAVE TESTED THE
DRUG AT 20 MPK, PEOPLE THOUGHT I
WAS CRAZY TO GO AS HIGH AS THAT
BUT I WANTED TO PROVE MY POINT
THAT AGGRESSION WAS COMPLETELY
BLOCKED AND NO EFFECT ON THE
PAIN RESPONSE.
>> THANK YOU.
>> YEAH.
>> OVER HERE AND HERE.
NVERY INTERESTING TALK.
DO YOU THINK THESE COMPOUNDS
THAT YOU'RE MAINLY USING IN
CHEEM OR THE--BUT ACTIVITIES AND
PROJECTSY INDUCED PERIPHERAL
NEUROPEN MEETINGALATHY WOULD
ALSO BE ACTIVE IN PEOPLE WITH
NERVE INJURY INDUCED
NEUROPATHIES SUCH AS AMPUTATION
NEUROMA, PAINFULLASMUTATION
NEUROMA MAY HAVE A PERIPHERAL
GENERATOR THAN A CNS SITE OF
ACTION, MAYBE A NONASTRO SIGHT
KIND OF THING.
>> I THINK THE EFFICACY WILL BE
LESS THAN THE 1S THAT I JUST
DESCRIBED, LIKE THE TRAUMATIC
NERVE INJURIES OR CHEMO THERAPY
EMPLOY SO WITH WE LOOK FOR
EXAMPLE, WHEN WE TART WITH
CARAGENEIN POST OP PAIN, YOU
NEED LARGE DOSES TO SEE AN
EFFECT EMPLOY SO SOME OF THESE
DOSES ARE, YOU KNOW 0-POINTS, 1
MPK, IN THESE MODELS YOU WE HAVE
TO GIVE 30 M PK,.
>> INTERESTING.
>> YEAH, THANK YOU >> THANK
YOU.
>> YEAH, SO MY SECOND QUESTION
WAS RELATED KIND OF TO THE
DRAWING YOU HAVE THERE AND ALSO
PART OF YOUR --
>> WHICH 1?
>> THAT PAINTING.
OF THE EFFECTIVE PART OF PAIN.
SO WE KNOW THAT 1 OF THE BIG
EFFECTS OF PAIN IS THE AFFECTED
CO-MORBIDITIES AND YOU INCLUDED
THAT IN YOUR INTRODUCTION SO I
WAS WONDERING, YOU MENTIONED
THAT YOU'VE DONE THE CPA, AND
CPP, I THINK.
>> CPP, NYEAH, CPPBUT I WAS
WONDERING IF YOU HAVE BECAUSE OF
THE TREMENDOUS POTENTIAL
THERAPEUTIC VALUE OF THESE
STROKES, HAVE YOU LOOKED AT THE
EFFECTS ON POTENTIAL LIKE
EFFECTIVE CO-MORBIDITIES OR YOU
KNOW BRAIN MECHANISMS OR THINGS
LOAMACYIC THAT.
>> NO, WE HAVEN'T -- WE HAVE NOT
DONE ANY OF THAT.
THE LAST EXPERIMENT THAT WE DID
BECAUSE WE'RE MOVING A LITTLE
BIT AWAY FROM SPINAL CORD IS
LOOKING AT THE RVM.
SO THAT PAPER, WE'VE ACTUALLY
DONE TRANSCRIPTOMICS SO THE
BOTTOM LINE IS THAT IF WE GIVE
THE COMPOUND IN THE RBM, WE CAN
ALSO REVERSE 92URE O PATHIC PAIN
AND SINGLE CELL RNASEQ IN THE
RBM AND IDENTIFIED SOME
INTERESTING PATHWAYS, ABOUT YOU
WE HAVE NOT DONE THOSE
EXPERIMENTS.
I THINK HERE, WE'VE GOT 14 YEARS
WORTH OF DATA, THAT BEING, YOU
KNOW PRODUCED REPRODUCED AND
ADVANCED BY MANY GROUPS, NOW YOU
HAVE CLINICAL EVIDENCE COMING
OUT THAT IT'S TIME TO REALLY
KIND OF THINK ABOUT REPURPOSING
AND FORGET ABOUT THE ANIMAL
WORK, THE DRUGS HAVE BEEN
APPROVED SINCE 2010 FOR MULTIPLE
SCLEROSIS, THESE PATE VS A
LITTLE BIT OF A FIRST ON DOSE, A
LITTLE CARDIA, IN .5% OF THE
PATIENTS, IT'S THE FIRST DOSE
BECAUSE THEY HAVE TO BE IN THE
CLINIC BUT THEN AFTER THE SECOND
DOSE, THERE'S NO BRADYCARDIA
WHATSOEVER.
THE NEWER DRUG HAVE AN IMPROVED
PROFILE BUT WE HAVE NOW 15 YEARS
WORTH OF DATA FROM HUMANS AND
WHERE WE'RE STUCK IS THE ABILITY
TO DO THIS CLINICAL TRIALS
BECAUSE WE DON'T HAVE THE DRUG
TO DO THE TRIAL AND THE MONEY.
SO, I THINK I'M GOING TO GO
START BANGING ON THE DOOR AGAIN
ON COMPANIES TO SEE IF THEY CAN
PROVIDE MONEY OR IF SOMEBODY
WANTS TO DO PROOF OF PRINCIPLE.
BUT AS I MENTIONED THEY'RE
MOVING FORWARD FOR ULCRATIVE
COLITIS AND SORTING -- PSORAIS,
NO MORE ANIMAL WORK, GO WITH
HUMANS.
>> LAST QUESTION.
>> THANK YOU FOR THE WONDERFUL
TALK, I WAS WONDERING ABOUT
CENTRAL VERSE US PERRIFFERAL
CENTER FOR EXCELLENCE ON AGINGS,
I WAS WONDERING IF MOVING
FORWARD YOU COULD GIVE THEM
PERIPHERALLY INSTEAD OF INTRA
FECALLY, SO I WAS WONDERING HOW
THEY CROSS BLOOD BRAIN BARRIER
TOAC SENTUATE AND SINCE THEY
WERE DEVELOPED FOR MS
PERRIVEERAL DEC VERSUS CENTRAL
DISEASE, COULD YOU COMMENT ON
HOW TO PROGRESS THIS AND MOVE
FROM -- GIVE THESE THINGS
PERIPHERALLY.
NALL RIGHT, SO, WE DON'T -- WITH
THE ADMINISTRATION OF THE DRUGS
INTRA FECALLY WAS TO DISSECT THE
PATHWAY MECHANISTICALLY, ALL OF
THE OTHER SPRMS WE GIVE THE DRUG
ORALLY, THEY'RE ALREADY
AVAILABLE AND THEY GET INTO THE
CENTRAL NERVOUS SYSTEM
BEAUTIFULLY WELL.
SO WE DON'T HAVE TO WORRY ABOUT
THAT.
THEY WILL GET TO THE CENTRAL
NERVOUS SYSTEM VERY NICELY AND
THEY USE FOR MULTIPLE SCLEROSIS
FOR THAT, SO CNS PENETRATION IS
NOT AN ISSUE FOR THESE DRUGS.
>> OKAY, WELL, THANK YOU SO MUCH
DANIELA, THANK YOU FOR YOUR
PIONEERING WORK NTHANK YOU.
>> [ APPLAUSE ]
NAND FOR YOUR DETERMINATION TO
BRING YOUR CONCEPTS TO
TRANSLATION TO ULTIMATELY REDUCE
PATIENT SUFFERING.
>> THANK YOU SO.
>> THANK YOU, THANK YOU VERY
MUCH EVERYONE.
YOU'RE NOW INVITED TO THE
RECEPTION OUTSIDE.
[ APPLAUSE ]