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LIVE – Translating Genetics into Medicine, April 25, 2019, 8:30 AM – 6:00 PM, The New York Academy of Sciences, 7 World Trade Center, 250 Greenwich St Fl 40, New York

April 25, 2019 by 2012pharmaceutical

LIVE – Translating Genetics into Medicine, April 25, 2019, 8:30 AM – 6:00 PM, The New York Academy of Sciences, 7 World Trade Center, 250 Greenwich St Fl 40, New York

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Translating Genetics into Medicine

Thursday, April 25, 2019, 8:30 AM – 6:00 PM

The New York Academy of Sciences, 7 World Trade Center, 250 Greenwich St Fl 40, New York

Presented By

The Biochemical Pharmacology Discussion Group

The first genome-wide association studies (GWASs) began unraveling the genetic basis of complex diseases over a decade ago. In that time, the development of innovative analytical and experimental methods enabled genomic data to inform how genetics relates to human traits, health, and disease. Nevertheless, progress has stalled in translating genetic association signals to an understanding of their underlying biological mechanisms, in identifying causal links between genetic variants and phenotypes, and in developing therapies based on this knowledge — few drug targets identified through GWASs have advanced.

This symposium will highlight emerging strategies to experimentally and computationally identify and validate causal association from patient cohorts, and outline the challenges and opportunities in translating GWAS hits into successful drug discovery programs.

Key Speakers

Richard P. Lifton, MD, PhD

The Rockefeller University

Robert Plenge, MD, PhD

Celgene

SOURCE

https://www.nyas.org/events/2019/translating-genetics-into-medicine/

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Translating Genetics into Medicine

Thursday, April 25, 2019

Keynote Speakers
Richard P. Lifton, MD, PhD
The Rockefeller University
“From Genes and Genomes to Targets and Therapies”Robert Plenge, MD, PhD
Celgene
“Making Medicines in the Future: Humans as a Model Organism”

This symposium will highlight emerging strategies to experimentally and computationally identify and validate genetic associations, explore the biological mechanisms of genetic variants and their link to phenotypes, and outline the challenges and opportunities in translating genome-wide association study (GWAS) hits into successful drug discovery programs.

For the full list of speakers and meeting agenda, please visit nyas.org/genmed2019

Program Support

Biochemical Pharmacology Lead Supporters

Biochemical Pharmacology Supporter

Biochemical Pharmacology Member

American Chemical Society New York Chapter

https://mailchi.mp/nyas/genmed_2019_04_04?e=2d875d53e9

Agenda

https://event.crowdcompass.com/genmed2019/activities

#GenMed2019

Thu, April 25th, 8:30 AM – 9:00 AM

Continental Breakfast and Registration

Translating Genetics into Medicine

Thu, April 25th, 9:00 AM – 9:15 AM

Introduction and Welcome Remarks

Translating Genetics into Medicine

Thu, April 25th, 9:15 AM – 9:45 AM

Precision Medicine in Obesity — The Value of Genetic Information

Session 1: Linking Disease to Genetic Variation

Translating Genetics into Medicine

Description

With a growing understanding of the genetic basis of diseases, the expectation is that genetics will soon revolutionize health care. Knowing a patient’s genome would enable us to predict risk of future disease more accurately and to prescribe personalized treatment strategies, as opposed to the traditional “one-size-fits-all” approach.Online genomic companies offer genetic testing directly-to-consumers (DTC), many of which focus on diet, nutrition, physical performance, and fitness. They claim that, based on their customer’s genotype data, they can they can design “genetically matched-diets” to help them lose weight more easily, determine what nutrients their body favors during exercise, what type of training is most effective, among others. Besides personalizing recommendations to live healthier lives, genetics is also being used to predict future risk of disease, such as obesity, using polygenic risk scores (PRSs). PRSs assess an individual’s overall genetic risk based on the cumulative effect of many common genetic variants. Some claim that a PRS can identify people-at-risk early in life, allowing prevention to start at a young age.I will discuss the scientific evidence currently available that supports (or not) personalizing lifestyle recommendations and predicting obesity based on genetic information. I will also briefly review the potential implications of inaccurate “genotype-driven” recommendations. For now, it seems that genotype-based recommendations are likely as effective as the “one-size-fits-all” recommendations and that current PRS prediction of obesity is outperformed by family history.

Speakers

Ruth Loos, PhD

Icahn School of Medicine at Mount Sinai

Presenter
mutations LEP Leptin agonist for Leptin deficiency Mutations on POMC, LEPReceptor MC4R agonists
Common obesity vs LEP deficiency,
Genetics in early age
Health weight Screening on exosome, genome transcriptome,
treatment based on genetic profile c
– response vs Direct-to-consumer: bold adviceompanies use data from 23 and me and offer protpcols for health weight
Saturated Fat diet – Framingham Offspring = show predicted data
longitudinal group not affected by high saturated died
no actual dat ahigh fat dairy high interactionAPOA2, APOA2CC
avoid fast food limiting meat
Score did not capture extreme obese, score is not predictive
10% on top risk not predicts
Will knowing GENETIC Profile change behaviour??
Survey 23 diseases – 3600 participants
Odesity life risk and genetics — all other factors are critical
MCAR – Appetite suppression in the brain — suppresses appetite, satiety
Risk Score is like a flip coin

Thu, April 25th, 9:45 AM – 10:15 AM

Title to be announced

Session 1: Linking Disease to Genetic Variation

Translating Genetics into Medicine

Speakers

Christopher Brown, PhD

University of Pennsylvania
GTEx: Geno Type DeneExpression
every gene has genetics variations in expression regulatory
Any random SNP is an eQTL – most of these tags
Concept of co-localization: Chromosome position phenotyoe 1 & 2 No association to Association
GTEx explains 52% of GWAS hits Nearest gene, Not nearest Gene No co-localization
Disease genes enriched for tissue specific eQTLs: Tissue specific eGene vs Tissue shared eGene
Epigenomic fine-mapping: GWAS locus
Study design: BioBank Liver biopsies for bio-genomics profiling
MOST EXPRESSED GENES INTERACT WITH DISTAL OVER DISTANCE THAN PREDICTED BY NEAREST
tissue specific of cis-eQTLs: Liver specific vs shared: associated with enhancer overlap
hQTL discovery – are enriched for liver LT alpha
identify co-regulated histone marks and genes’ An Example: Chromosome 18 position common loci
new Biology; KPLB1 – FADS1/2/3
FTO: Chromosome 16
Novel candidate have distinct properties: proxemity searches not significant vs research #Brown Lab, Penn, GTEx,
Transcriptomes of 5000 liver biopsy tissues
DIseased Liver tissue

Presenter

Thu, April 25th, 10:15 AM – 10:45 AM

Identifying Gene Regulatory Mechanisms of Disease

Session 1: Linking Disease to Genetic Variation

Translating Genetics into Medicine

Description

Genetic variation that alters gene regulation contributes to many and diverse human diseases. In particular, there is strong evidence that nearly all common human traits and diseases are influenced to some degree by non-coding genetic variation that acts via changes in gene regulation. Even for rare diseases, there is evidence that regulatory variation can influence the severity of diseases. Nonetheless, there persist major technological challenges in our ability to empirically or computationally identify specific regulatory mechanisms contributing to those diseases. Overcoming those obstacles will greatly benefit human health by revealing new opportunities for disease diagnosis and treatment.I will discuss recent progress in this area, focusing predominantly on the development and use of new high-throughput genome-scale technologies to quantify the effects of non-coding genetic variation on human gene regulatory element activity and the regulation of downstream target genes. I will also discuss recent progress and specific case studies that highlight the use of those techniques to map causal regulatory mechanisms of various human traits and diseases. Finally, I will discuss future directions in those techniques, with an eye towards making the identification of non-coding mechanism of human disease routine.

Speakers

Timothy E. Reddy, PhD

Duke University

Presenter
Genotype and phynotype
enhancers dCas9-P300 reveals HKDC1 is the target gene – is a 5th human kinases
gRNA hexokinases: HK1,HK2, HK3 – gloucose in Blood,
HK4 (Glucokinase – diabetesis
Mice in pregnancy – heperglycemia
New hypothesis – hyperglycemia during pregnancy:3q25 adipose
STARR-seq reporter assays: GFP
MASSIVELY PARALLEL REPORTER ASSAY FROM PATIENT’S DNA – PCR-BASED
CHROMOSOME 3 POSITION: TRANSVERSION POP-STARR
rere alleles have greater and typically deleterious effects
Scaling up POP-STARR to entire GWAS loci
HepG2 cells: Coverage of target regionsL DIfferences in regulatory activity in pregnancy hyper glacenia
epigenome editing screens on HER2
CRISPR mapped to target genes: HKDC1 – gene not looked at before
expance and scale opportunity exists
Cell Type Model

10:45 – 11:15 – Coffee Break

Thu, April 25th, 11:15 AM – 11:20 AM

Genomic Screening and Personalized Medicine in a Highly Diverse Biobank in New York City

Session 2: Data Blitz Presentations

Translating Genetics into Medicine

Speakers

Noura Abul-Husn, MD, PhD

Icahn School of Medicine at Mount Sinai

Presenter
phenotypic complexity + de novo loss of function mutations
Chromatin remodeler mutation can lead to prevention of surgery is treated
Neuronal migration defect
cutaneous disorder caused by somatic mutationsMutations in KRAS, Ichthyosis with confetti
Deviations from Mendelian models: Variable expressivity, Incomplete penetrance
CVD: loss of function mutation FLT4 – Tetralogy of Fallot heterozygous mutation
Pulmonary fibrosis – short telemere – inhalation if MUTATION + Environment – disease will occur
Congenital Heart Disease + Autism – gene loss function mutation vs de Novo mutation
Non-syndromic midline craniosynostosis – SMAD6 mutations: common variant near BMP2 and SMAD6 for OSTEOBLAST differentiation – to cause Non-syndromic midline cranio-synostosis
Coming revolution in therapeutics: Rare diseasese and common diseases

20,000 genes – known and studies are 5,000

Thu, April 25th, 11:20 AM – 11:25 AM

Immune Disease Variants Modulate Gene expression in CD4+ Regulatory T Cells and Inform New Drug Targets

Session 2: Data Blitz Presentations

Translating Genetics into Medicine

Speakers

Dafni Glinos, PhD

New York Genome Center

Presenter

Thu, April 25th, 11:25 AM – 11:30 AM

Age, Sex, and Genetic Polymorphisms Influence the Inherent Patterns of Infiltrating Immune Cells

Session 2: Data Blitz Presentations

Translating Genetics into Medicine

Speakers

Andrew Marderstein

Weill Cornell Medicine

Presenter

Thu, April 25th, 11:30 AM – 12:15 PM

Keynote Address ~ From Genes and Genomes to Targets and Therapies

Session 3: Keynote Address

Translating Genetics into Medicine

Speakers

Richard P. Lifton, MD, PhD

The Rockefeller University

Presenter

Thu, April 25th, 12:15 PM – 1:15 PM

Networking Lunch and Poster Session

Translating Genetics into Medicine

Thu, April 25th, 1:15 PM – 1:45 PM

Human Genetics to Identify Vascular Causes of Coronary Artery Disease and Myocardial Infarction: From Discovery to Function

Session 4: Characterizing Functional Relevance of Genetic Variants

Translating Genetics into Medicine

Description

Coronary artery disease and myocardial infarction remain the leading causes of death in the United States and throughout the world. New treatments will require a better understanding of the casual pathways in the cells of the blood vessel wall, where the atherosclerotic plaque is formed. The genetic loci identified through genome-wide association studies (GWAS) represent new therapeutic targets, but only a small number have been functionally characterized. The majority of these risk loci are not associated with plasma lipid levels, suggesting they can identify novel vascular mechanisms of disease.We have prioritized the functional analysis of GWAS loci associated with multiple vascular diseases. One such locus is the 6p24 region, which is associated with five vascular diseases including coronary artery disease, migraine headache, cervical artery dissection, fibromuscular dysplasia and hypertension. Through genetic fine mapping, we prioritized rs9349379, a common SNP in the third intron of the PHACTR1 gene, as the putative causal variant. Epigenomic data from human tissue revealed an enhancer signature at rs9349379 exclusively in aorta, suggesting a regulatory function for this SNP in the vasculature. CRISPR-edited stem cell-derived endothelial cells demonstrate rs9349379 regulates expression of endothelin 1 (EDN1), a gene located 600 kb upstream of the associated SNP. The known physiologic effects of EDN1 on the vasculature may explain the pattern of risk for the five associated diseases. Overall, these data illustrate the integration of genetic, phenotypic, and epigenetic analysis to identify the biologic mechanism by which a common, non-coding variant can distally regulate a gene and contribute to the pathogenesis of multiple vascular diseases.

Speakers

Rajat Gupta, MD

Broad Institute, Massachusetts General Hospital, and Harvard Medical School

Presenter
Lipid-related therapies vs Non-lipid Therapeutics
successful clinical Trials;
IL- 3B Inhibitor by Novatris
Endothelin-1 is a vasoconsrtictive peptide secteated by endothelial cells
Higher ET-1 secretion Genome editing 1bp change at SNP was technically difficult
2-step Cas9 editing at rs9349379
EDN1 vs 6p24 locus, downstream doe ET1
higher circulating endothelin-1 in participants with risk genotype
Vascular biology ET-1 protein,
ET-A – brain
ET-B – kidney
EDNRA – ET-1 Increase CAD/MI decrease HTN – veaodiletion
distal genes
human genetcs variants with pleiotropic effects that the on-target effects predict consequences of other disease

Thu, April 25th, 1:45 PM – 2:15 PM

New Tools for High-throughput Functional Characterization of the Human Noncoding Genome

Session 4: Characterizing Functional Relevance of Genetic Variants

Translating Genetics into Medicine

Description

CRISPR/Cas9 has driven forward the validation of candidate regulatory elements by enabling high-throughput endogenous perturbation of the human noncoding genome. These advances have been enabled by Cas9’s suitability for use in pooled approaches to perturb and phenotype thousands of candidate regulatory elements in a single experiment. In my talk, I will cover two advances for pooled CRISPR/Cas9 screens of the noncoding genome. First, I’ll describe a method we devised to scan thousands of kilobase-sized deletions (“ScanDel”) across a desired region, programming one unique deletion per cell in a pool and phenotyping them in multiplex by pooled functional selection. In our proof-of-concept study, we used ScanDel to program 4,342 overlapping 1-and 2- kilobase (Kb) deletions that covered 206 Kb centered on HPRT1, the gene underlying Lesch-Nyhan syndrome. However, ScanDel and its contemporaries are limited to evaluating regulatory elements for their effect upon a single gene. To overcome this, we designed and implemented a second method in which large numbers of CRISPR perturbations are introduced to each cell, followed by single-cell RNA-seq to read out their effect upon any transcript. We designed CRISPR perturbations to 5,920 candidate regulatory elements in the K562 cell line, and tested for differential expression of all expressed genes within 1 megabase of each candidate enhancer. We thus effectively evaluated >70,000 potential enhancer-target gene relationships in one experiment, and associated 664 enhancer-gene pairs. Pooled perturbation methods of this scale are poised to facilitate the comprehensive elucidation of the gene-regulatory landscape of the human genome.Coauthors: Andrew J. Hill, Greg Findlay, José L. McFaline-Figueroa, Melissa D. Zhang, Anh Leith, Cole Trapnell, and Jay Shendure, University of Washingon; Nadav Ahituv, University of California San Francisco.

Speakers

Molly Gasperini

University of Washington

Presenter
study single gene at a timemonogenic screens can only
location of enhancers eQTL mapping is a masssive parallel methods to test all variants –
GWAS “synthetic variation” insert randomly CRISPR candidate enhancer vs target gene
CRISPRi – for Epigenetics monoclonal lines
crisprQTL mapping: Assay formarly known
Multiplex enhancer-gene pair screen
Leukhemia cell line K562: Open chromatin, RNA POL II
Lentivirus – high multiplicity equ 5.8 million cells
detected 664 enhancer-gene pairs eMNU – enhancers gene pairs
distance between enhancers and thier target genes
monogenic pooled deletion scan vs multiplexing whole transcriptome enhancer-gene pair screen

Thu, April 25th, 2:15 PM – 2:45 PM

From Functional Genomics to Translational Therapeutics for Cardiometabolic Disease

Session 4: Characterizing Functional Relevance of Genetic Variants

Translating Genetics into Medicine

Description

The application of genome-wide approaches to the study of cardiometabolic disease and its risk factors is having a major impact on our understanding of this complex disease and our ability to prevent and treat it. Genome-wide common and rare variant studies and subsequent functional genomics approaches have provided important new insights into the biological pathways involved in lipoprotein metabolism, diabetes, fatty liver disease, atherogenesis, and cardiomyopathy. When these genomic data are coupled to human phenomic science, the potential for new information related to human health and disease is immense. The application of Mendelian randomization is allowing important inferences with regard to the causality of new cardiometabolic risk factors.The intense focus on human genetics is leading to the identification of new therapeutic targets. Functional genomics studies based on these new targets is helping to understand disease pathogenesis and pointing to more precise approaches to therapies. Wider application of genetic testing in the clinical arena is likely to lead to greatly improved risk stratification and personalization of preventive and treatment paradigms. The field of cardiometabolic disease has been at the forefront of translating genetics into medicines.

Speakers

Daniel J. Rader, MD

Perelman School of Medicine, University of Pennsylvania

Presenter

Thu, April 25th, 2:45 PM – 3:15 PM

Networking Coffee Break

Translating Genetics into Medicine

gene burden LMNA Cardiomyopaty – LOF
REVEL – 40 carriers of deleterious variants with heart failure
Exome-wide LOF gene burden
Common variANT – TRIB1 VARIANTS: ADIPOKINES, LIVER FAT AND ENZYME, CAD, TG – LDL-C HDL-C
SLC39A8 GENOMIC LOCUS IS ASSOCIATES – A METAL MAGNESENE-DEPENDENT ENZYME – schesophrenia – magnesene related

Thu, April 25th, 3:15 PM – 3:45 PM

Fueling a Genetics-driven R&D Organization

Session 5: Emerging Opportunities in Genetics for New Therapeutics

Translating Genetics into Medicine

Description

Discovering and developing new medicines that are safe and more highly effective than existing therapies is an increasingly challenging and expensive endeavor. Over the past decade, human genetics has given us new insights into the biology of disease and clues into how to approach the discovery of new drugs that are more likely to be successful. The challenge for would-be drug discoverers is to gain access to powerful sources of genetic associations, understand their impacts on health and disease, disentangle the underlying causal mechanisms, and amongst the many options, choose the proteins that will provide the best drug targets.

Speakers

Matthew Nelson, PhD, MA

GlaxoSmithKline

Presenter
2013 – 2014 – case studies at GSK disease via genomics using the Human as the organizm for drug development since Human genome is only human’s.
Genetics support between indication and therapeutics
UK Biobank – subject-based genetic data

diversity of phenotypes
exome seqencing – 2021 Regeneron + 5 big Pharma – collaboration
GWAS analysis of osteoarthritis in iBiobank – 64loci
GWAS and asthma – onset child or adult
PheWAS vs GWAS – 500,000 individuals
PheWAS – IL33 LOoF – SNVs proxies for target pertubation

Thu, April 25th, 3:45 PM – 4:30 PM

Keynote Address ~ Making Medicines in the Future: Humans as Model Organism

Session 5: Emerging Opportunities in Genetics for New Therapeutics

Translating Genetics into Medicine

Description

Human genetics offers the potential to transform drug discovery. However, the path from a human genetic discovery to a new medicine remains challenging. An “allelic series” model is a concept that offers one solution to utilize human genetics for decision-making along the drug discovery journey. There are several compelling examples in immunology that fit with the allelic series concept, including TYK2 and IL2RA. Extrapolating from these and other examples, it is conceivable to build a genetic dose-response portal in the near future.

Speakers

Robert Plenge, MD, PhD

Celgene

Presenter

50%-80% TYK2 effective without infection risk increase or JAK1,2,3 activation

IKZF1 – Common variants associated with SLE, T1D, IBD, allergy, B-cell ALL, blood cell counts and more
Rare variants associate with
Common variant GSAW Lead SLE SNP
Rare LoF mutations associated with immune deficiency: Low Ig, Pleiotropic effect of other common allele
matching modality to mechanism
HOW to build a genetic dose-response portal

Thu, April 25th, 4:30 PM – 5:00 PM

Panel Discussion: The Future of Transformational Genetics

Session 5: Emerging Opportunities in Genetics for New Therapeutics

Translating Genetics into Medicine

Speakers

Christopher Brown, PhD

University of Pennsylvania

Presenter
Ruth Loos, PhD

Icahn School of Medicine at Mount Sinai

Presenter
Matthew Nelson, PhD, MA

GlaxoSmithKline

Presenter
Robert Plenge, MD, PhD

Celgene

Presenter
gene function LoF GoF
Pick a human phenotype for
drug efficacy – Human Phenotype
effect of multiple phenotype as proxy for ADEs on efficacy and toxicity
New target for drug screens

Immunotherapy Example

Allelic series model TYK2
common protein reduce TYK2 – IL23A IL12B signaling and psoriasis
TYK2 – Typw 1 Biabetis RA
Variants: Autoimmunity: If knock out risk of Infection
InfectionsP1104A; protective from multiple autoimmune disease
I684S ANAOTHE
PARTIAL JAK 1,2,3,

Thu, April 25th, 5:00 PM – 6:00 PM

Networking Reception and Poster Session

Translating Genetics into Medicine

Thu, April 25th, 6:15 PM – 6:15 PM

Adjourn

Translating Genetics into Medicine

Posters

Please see attached pdf below to view the poster abstracts.

1. Noura Abul-Husn, MD, PhD, Icahn School of Medicine at Mount Sinai, Genomic Screening and Personalized Medicine in a Highly Diverse Biobank in New York City

Margot Brandt, New York Genome Center, Validation of cis-Regulatory Transcript Variants Using Fine-mapping and CRISPR/Cas9 Genome Editing
Olof S. Dallner, PhD,The Rockefeller University, Dysregulation of a long noncoding RNA by Genetic Variants Reduces Leptin Leading to a Leptin Responsive Form of Obesity
Dafni Glinos, PhD, New York Genome Center, Immune Disease Variants Modulate Gene expression in CD4+ Regulatory T Cells and Inform New Drug Targets
Scott MacDonnell, PhD, Regeneron Pharmaceuticals, Using iPS Derived Cardiomyocytes to Identify Casual Links Between Genetic Variants and Phenotypes – Case Study Using MYH7 R403Q as a Model of Hypertrophic Cardiomyopathy
Andrew Marderstein, BS, Weill Cornell Medicine, Age, Sex, and Genetic Polymorphisms Influence the Inherent Patterns of Infiltrating Immune Cells
Christian Stolte, New York Genome Center, Turning WGS Genetic Testing into a Dialogue Between Physicians and Labs with GenomeDiver
Archana Tare, MS, Albert Einstein College of Medicine, Integrated Analysis of Deep Sequencing and Functional Genomics Identifies SMAD3 as a Therapeutic Target for Longevity and Healthy Aging in Humans
Fang Wang, Temple University School of Pharmacy, Using Integrative Bioinformatics Analysis to Reveal Novel Drug Repurposing Targets for COPD
Junke Wang, MS, The Ohio State University, Genome Wide Association Analyses Identify Pleiotropic Variants Associated with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Susceptibility