Rare, metabolic, and undiagnosed diseases with Pramod Mistry

Transcript

• 00:13Welcome back to Yale Liver
• 00:15Diamond Jubilee event.
• 00:16The Q&A for the afternoon
• 00:18sessions will take place at 3:15.
• 00:20This session is being recorded.
• 00:22Thank you. Welcome to our the
• 00:26second talk in our series and
• 00:28I'm Cliff boat and I'm proud
• 00:31to introduce Prim mystery,
• 00:32who's professor of medicine at the
• 00:34Yale School of Medicine and director
• 00:36of the Lysosomal Disease program,
• 00:38and he'll be speaking to us
• 00:40today around on rare metabolic
• 00:42and undiagnosed diseases.
• 00:50Thank you so much Cliff
• 00:52for your kind introduction.
• 00:55I want to thank Michael Nathanson and
• 00:58Mario Strasser Bosco for including
• 01:00the topic of friend metabolic
• 01:03and undiagnosed liver diseases in
• 01:05the time and Jubilee celebration.
• 01:08It is appropriate to start with our founder.
• 01:13I want to go to the next slide.
• 01:15It is appropriate for us
• 01:18to start with our founder.
• 01:20Who was affectionately called
• 01:22by his colleagues at Yale,
• 01:23New Haven Hospital and his students
• 01:27as General Classic and DRD.
• 01:29The Doctor of rare diseases.
• 01:32His renowned clinical acumen was
• 01:34underpinned by his ability to treasure
• 01:37the exceptions in his clinical
• 01:40practice annunciated by the renowned
• 01:43British geneticist of early 20th century.
• 01:46The most dramatic illustration of
• 01:49the importance of this approach is
• 01:51the work of Brown and Goldstein.
• 01:54Who's stratified cholesterols
• 01:56syndromes and found the exceptional
• 01:59patients and discovered LDL receptor
• 02:02using skin fibroblast cell lines.
• 02:05One year after they won the Nobel Prize,
• 02:09Joe Goldstein in his presidential
• 02:11address to the American Society of
• 02:14Clinical Investigation bemoaned the
• 02:16plight of academic investigators and
• 02:19issued a prescription for the syndrome
• 02:21that he calls called paralyzed academic.
• 02:24Investigate the syndrome.
• 02:26And the prescription was to obtain
• 02:29technical scientific training
• 02:31and show technical courage.
• 02:34Implicit in this was the essential
• 02:37clinical skills to recognize
• 02:40the exceptional patient and now.
• 02:42Armed with the access to genomic analysis,
• 02:46every patient on our task in service
• 02:49and liver transplant service is such
• 02:52an exceptional patient displaying
• 02:54unique genetic vulnerabilities to
• 02:57develop end stage liver disease.
• 02:59This knowledge is transforming hepatology
• 03:02practice as vividly illustrated by
• 03:05Sylvia Villarino's Trail Brave trail,
• 03:09blazing world.
• 03:11I think Doctor Katzkin would be very proud
• 03:14to see that we have national destination
• 03:17programs in undiagnosed liver disease,
• 03:20Wilson's disease,
• 03:22lysosomal diseases,
• 03:23and inherited collegiality.
• 03:25But probably the world's largest
• 03:28biorepository and Natural History data.
• 03:31I was thinking about this.
• 03:35Oh, I'm sorry.
• 03:36One of my slides is missing.
• 03:38I was bragging about this to a
• 03:41colleague of mine and he asked
• 03:43me what are you going to do with
• 03:45all this and I've been thinking
• 03:47ever since about the question and
• 03:50asking how do we honor the immense
• 03:53gifts of patients that we follow
• 03:55providing Natural History data and
• 03:58bio samples to advanced clinical
• 04:00and basic science to benefit this
• 04:03underserved patient population.
• 04:05Who often feel neglected and
• 04:08deeply stigmatized?
• 04:10So right diseases are very important.
• 04:12They are defined as conditions that
• 04:15affect less than 200,000 people in
• 04:18the United States and collectively
• 04:21it affects one in ten Americans.
• 04:24Many of these disorders involve the liver,
• 04:27either as a primary site of metabolic
• 04:30defect or as part of Multisystemic disease,
• 04:33and typically patients see many
• 04:36different physicians up to about
• 04:3820 years with the mean of about.
• 04:40Five years to receive the correct diagnosis.
• 04:44Sadly, many remain undiagnosed,
• 04:46such as with diagnosis of natural D,
• 04:50even alcoholic liver disease,
• 04:52cryptogenic, cirrhosis.
• 04:53They remain a significant burden
• 04:56of hitherto unknown genetic phase
• 04:59syndromes causing liver disease,
• 05:01as is being exemplified by
• 05:04Sylvia Villarino's work.
• 05:05Importantly,
• 05:06what Brown and Goldstein taught us
• 05:09is that understanding rare diseases
• 05:13confers the ability to transform
• 05:15understanding of common diseases,
• 05:17such as with familial hypercholesterolemia,
• 05:20statins, and PCSK.
• 05:229 inhibitors.
• 05:24So this was the slide I
• 05:26was talking to earlier,
• 05:27and so patients are coming to see us from
• 05:31all over the country year after year,
• 05:34allowing us to capture.
• 05:36Giving us the privilege to take care of them.
• 05:39Collecting Natural History data,
• 05:42providing bio samples.
• 05:44And I was bragging about this to a senior
• 05:47physician scientist and he said to me,
• 05:50well,
• 05:50what are you going to do with
• 05:53all this enormous gifts that are
• 05:55given to you by your patients?
• 05:57How are you going to honor these
• 06:01gifts and then translate that to?
• 06:06Important questions to advance clinical
• 06:09science and help these patients.
• 06:13So here is the overarching premise
• 06:16based on lysosomal disease
• 06:18program that is being further
• 06:21advanced by Sylvia Pellegrino in
• 06:24her undiagnosed disease program.
• 06:26We've taken chocos since message to
• 06:29heart with everything beginning and
• 06:31ending with our patients and reverse
• 06:34translation to assemble unparalleled
• 06:37expertise in murine and humanized models.
• 06:41Sidelines,
• 06:41including I PSC headlines and
• 06:44application of genomics single cell
• 06:48transcriptomics biomarker discovery,
• 06:51and clinical trials,
• 06:52as Michael Matthews, Nathansen described,
• 06:55the culture of men.
• 06:56Mentorship is in the very fabric
• 06:59of our center to train the next
• 07:02generation of physician scientists
• 07:04and to provide pastoral care of
• 07:07these gifted upcoming individuals
• 07:08in this challenging times,
• 07:11when these individuals better
• 07:14on disproportionate burden.
• 07:16And so the major themes of our rare
• 07:19metabolic and diagnosed living
• 07:20liver disease program is to achieve
• 07:23the best outcomes for patient.
• 07:25To provide compassionate holistic care
• 07:28and advocacy and compile disease registry.
• 07:32And it has to be high science driven
• 07:36involving advanced disease modeling,
• 07:38iterative translation to patients to
• 07:41overcome the known limitations of
• 07:43murine models and then generating.
• 07:46Biomarker discovery and validation
• 07:49in patience to enhance patient
• 07:52management and enrich clinical
• 07:54trials involving transcriptomics,
• 07:57proteomics and also hypothesis
• 08:00driven candidate biomarkers.
• 08:02We are applying all mixed to investigate
• 08:04all of the disease beyond the liver.
• 08:07For example, the brain.
• 08:08I think when a hepatologist looks,
• 08:11for example at neuroinflammation
• 08:14or neurodegeneration using
• 08:17the current technologies,
• 08:18I believe that we bring the very special
• 08:22insight that cannot be provided if
• 08:25this components of the disease are
• 08:29studied by different specialities.
• 08:31And we provide the entire repertoire
• 08:35of therapies for genetic diseases,
• 08:38including liver transplantation
• 08:40and surgical gene therapy,
• 08:42but also gene therapies,
• 08:44including RNA and recombinant
• 08:47enzymes and small molecules.
• 08:50I think an area that I'm very
• 08:53excited about is the relevance
• 08:55of our rare disease endeavor to
• 08:58provide novel insights into disease
• 09:01mechanisms and novel therapeutic
• 09:04targets for common diseases.
• 09:07And so let's start with clinical care,
• 09:09and this is a paper that is about to
• 09:11be submitted from the International
• 09:13Group share registry that that shows
• 09:17extraordinarily high risk of cancer.
• 09:21It is for hematological cancers,
• 09:23including multiple myeloma
• 09:25and non Hodgkin's lymphoma.
• 09:27But remarkably,
• 09:28there is an increased risk of
• 09:31hepatocellular carcinoma even
• 09:32in non cirrhotic liver as well
• 09:35as renal cause renal cell.
• 09:37Arsenova,
• 09:37so this is a study being compiled
• 09:40with an international registry,
• 09:43but the foundational work for this
• 09:45study was laid at Yale in 2010,
• 09:48and this was a study that was led by
• 09:51Tamar Taddy and she looked at 406
• 09:55patients with Gaucher disease and
• 09:57found that overall cancer risk and
• 10:00demonstrate disease was increased,
• 10:03and particularly for multiple myeloma.
• 10:05Non hematologic.
• 10:06Answers and so this was the first
• 10:10demonstration of potential role
• 10:13of toxic glucosylceramide single
• 10:15lipids and carcinogenesis.
• 10:17Moreover,
• 10:18what tomorrow showed was that
• 10:20when she compiled Kaplan Meyer
• 10:23curves for polyclonal dermopathy
• 10:25monoclonal dermopathy of unknown
• 10:28significance and multiple myeloma,
• 10:30it immediately tells you that this
• 10:34lipid laden activated macrophages are
• 10:37talking to be lymphocytes and this
• 10:40led to a series of insightful studies
• 10:43by my colleague and lab member,
• 10:46Shiny Nair.
• 10:48Once it is long term question,
• 10:51which is that you can have
• 10:53massive splenomegaly in patients
• 10:55with calcium disease.
• 10:56And yet if you analyze the amount of lipids,
• 10:59it is barely 2% by weight and so the
• 11:03question is what is going on once the
• 11:07glucosylceramide lipids are accumulating?
• 11:10And what Chinese showed is that the
• 11:14macrophages are presenting the lipids
• 11:16in the context of CD1 molecules.
• 11:20And yeah,
• 11:21recognized by T cell receptors on a
• 11:24specific sub top subtype of NKT cells
• 11:28that harbor follicular helper phenotype.
• 11:31And this interaction leads to activation
• 11:35of germinal Center B lymphocytes
• 11:38and production of anti lipid,
• 11:41lipid reactive antibodies and
• 11:43if this process continues it
• 11:46eventually leads to gammopathy
• 11:49and multiple myeloma development.
• 11:51The lipid laden macrophages.
• 11:54Very interesting because there
• 11:56are a number of biomarkers that
• 11:59one can use in clinical practice,
• 12:02listed here, but also they.
• 12:04They expressed macrophage mannose
• 12:06receptor which is a way to
• 12:09get hold of you take enzyme molecules
• 12:12into the lysosomes of these macrophages.
• 12:15This concept has been advanced
• 12:19by showing that in fact these.
• 12:23Anti lipid antibodies can activate
• 12:26the complement and the C 5A so
• 12:30generated binds with the C 5A receptor,
• 12:33and paradoxically it increases the
• 12:37production of glucosylceramide synthase,
• 12:39making more of the lipids.
• 12:41So here we have an enzyme deficiency,
• 12:44and paradoxically this inflammatory
• 12:46pathway is leading to greater production
• 12:50of the lipid or positive feedback loop.
• 12:53And and this has led to a novel therapeutic
• 12:57target inhibitor of glucosylceramide
• 13:00centers which underwent clinical trials,
• 13:03and we were the principal center in a
• 13:08multi multinational study and it is now
• 13:11an approved drug with broad implications.
• 13:18And so this pathway has clearly
• 13:21relevance to common disease.
• 13:23So here shiny working with the mother
• 13:27showed that about 1/3 of sporadic
• 13:31multiple myeloma patients have their
• 13:34paraprotein that reacts to that shame.
• 13:37Lipids. Not only that,
• 13:39it reacts to another Lysol lipid
• 13:42called lysophosphatidylcholine,
• 13:45which we believe.
• 13:46He's a player in fatty liver disease,
• 13:50and interestingly,
• 13:52the genetic stratification of
• 13:54this lipid reactive come up.
• 13:56They showed that there were chromosome
• 14:001Q21 abnormalities that were
• 14:02enriched in this patient population,
• 14:04and this is the locals
• 14:07that harbors the GBA gene.
• 14:10So this is the pathway that
• 14:12we've delineated in the Golgi
• 14:16glucosylceramide synthase.
• 14:18Activity leads to production of
• 14:20glucosylceramide and in the lysosome.
• 14:22This lipid is turned over and
• 14:26we went glucosylceramide.
• 14:27Cerebral side is sufficient.
• 14:29It activates an alternative
• 14:32pathway to get rid of this,
• 14:34accumulating lipid via the enzyme
• 14:37and said ceramic days to produce
• 14:40glucosides sphingosine and that
• 14:42allows the cell to export this
• 14:46lipid out of the cytoplasm.
• 14:48And at least advocate the cellular toxicity,
• 14:51but it causes other downstream problems.
• 14:55These lipids are cumulating are very
• 14:58potent inflammatory molecules as
• 15:01ligands for the MINKEL receptor and
• 15:04it generates anti lipid antibody.
• 15:07As I showed you and this downstream
• 15:10lipid has extreme potency as a
• 15:13bio active lipid and actually
• 15:15mediates a lot of the pathological.
• 15:19Manifestations of God, shade,
• 15:21disease and,
• 15:22importantly,
• 15:22the event on to validate this as a serum
• 15:26biomarker to be used in clinical trials,
• 15:29and this is one example in the
• 15:32Phase 223 clinical trials that
• 15:35they conducted where you are seeing
• 15:38biomarker responses to inhibitor
• 15:41of glucosylceramide synthase and
• 15:44what it shows is a Gaussian lipids,
• 15:47GL1 and lyso GL.
• 15:49Prasad single saying,
• 15:50have dramatically reduced and
• 15:53this marker of alternatively
• 15:56activated macrophage cytotoxicity
• 15:58days is concurrently reduced,
• 16:01as is a chemokine CCL 18 which is
• 16:04involved in T cell and B cell recruitment
• 16:08to liquidate an antigen presenting cells.
• 16:12So one of the central.
• 16:15A problem in Goshen disease management is,
• 16:19you know,
• 16:20topic diversity.
• 16:21There was great expectation that
• 16:23when you found once you found
• 16:26the genotype of Gaucher disease
• 16:28mutations then we will be able
• 16:30to predict prognosis accurately.
• 16:32This is the most common genotype
• 16:35in New York metropolitan area and
• 16:38you can see here the the onset
• 16:41of clinical manifestation can
• 16:43be in childhood and my oldest.
• 16:45Conditions are in their 70s or
• 16:48even 80s and you get the same
• 16:51kind of phenotypic diversity
• 16:53in other genotype groups.
• 16:56Although that is an overall true
• 16:59correlation such that this is
• 17:02the mildest phenotype and this
• 17:04is the most severe phenotype.
• 17:07So our goal has been to discover
• 17:10the modified genes,
• 17:11and I'm sure you've heard from
• 17:13workers in many other fields that
• 17:16this is has been the Holy Grail.
• 17:19And we decided to do a China
• 17:22Wide Association study,
• 17:23thinking that if we just selected
• 17:25the N 370 as homicidal statements,
• 17:28which are all Ashkenazi Jewish,
• 17:31and they have a founder mutation
• 17:34from 10th century that there are
• 17:36regions in the genome that are
• 17:39shared, and we may throw up a
• 17:42candidate modifier gene. And I'm sorry
• 17:46it's 236 we got we're running
• 17:48over so. To wrap it up,
• 17:50OK, so if I'm going to wrap this
• 17:53up after the next slide and.
• 17:56And we found a signal on a lipid sensor.
• 18:01Genes, CNA and this will be my last slide,
• 18:06so we were semble the largest
• 18:09cohort ever of 580 patients.
• 18:12International cohort to
• 18:13look at smart sequencing.
• 18:16Looking at this very gene dense
• 18:18region in the human genome.
• 18:21To look at this adjacent
• 18:23genes for modified genes in.
• 18:25I don't love the whole exome sequencing,
• 18:29so with that I will end and I
• 18:31apologize for going over time.
• 18:34Thank you, Fran. That was great.