Alan Shuldiner, DiscovEHR(y) of new drug targets and the implementation of precision medicine.

Alan Shuldiner, Regeneron Genetics Center.

A lot of R&D dollars are spend on new drugs, and the vast majority fail, and mainly in late phases for lack of efficacy.  Pre-clinical models that get you that far, just aren’t good predictors of efficacy in Humans.

Successful use of genetics based approaches:

Example with PCSK9, which led to PCSK9 antibodies. (2003 -> 2012)

Example with Null APOC3, which led to antisense inhibitors (2008 -> 2015)

Target discovery is great application.  Also: Indication discovery, Biomarkers and De-risking.

Created “Ultra high-thgouthput sequencing and analysis at regeneron”, focus on exomes.  200,000 samples prepped per year.   Sequencing 150,000 samples per year. Cloud based  platform, DNA nexus involved.

What do they sequence?  General populations, family studies, founder populations, phenotype specific cohorts.

Mendelian disease collaborations:  126 families with novel disease genes, 92 with novel variants in known genes…  some others that have not yet been solved.

DRIFT consortium: discovery research investigating founder population traits.

Geisinger-Regeneron DiscovEHR Collaboration: comprehensive genotype/phenotype resource combing de-identified genomic and clinical data. Transform genotype into improvements in patient care.  >115,000 patients in the biobank.  60,000+ exomes sequenced.  Large, unselected population.  Some focus on specific conditions where data is particularly interesting.

Constantly growing library of phenotypes to associate with genomic studies.  Includes some case/control, rich quantitive traits, measurements like EKGs.

Discovered over 4 Million variants – vast majority have frequency < 1%.   (from 50,726 patients)

Some examples of how the data is being put to use. Protective variant for cardiovascular disease.

What if everybody’s genome was available in their EHR – GenomeFirst program.

Return results that are actionable into EHR.  56 ACMG genes + 20 new ones they believe are actionable.   Exome is done in non-CLIA, but a second sample is done in a CLIA environment to confirm.

in 50,000 exomes, ~4.4% of study participants will test positive for one of the actionable events.

This has helped early diagnosis become much more effective and allows preventative treatment.

Conclusions:  Genome based discovery for drug design, actionable items possible, and can have a huge impact on human health.

 

 

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