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Large-Scale Genetics Research: Q&A with Aris Baras

With genetic data making headlines, Aris Baras reflects on how genetic research can further advancements in medicine and delves into how his team’s work on large-scale approach is paving the way for new discoveries and enhanced patient care.

How can understanding human genetics benefit medicine?

Human genetics is one of the most powerful approaches available in drug discovery and development today. One of the biggest bottlenecks remaining in drug discovery is the identification of well-validated targets. Drugs developed with human genetics evidence, supporting the selected target, have historically had substantially higher success rates. At a time where the entire industry is competing over many of the same targets and where few have human genetics validation, the ability to identify and validate novel targets for important diseases is a must-have capability and one that can be unlocked by human genetics.

How are you approaching genetics research at Regeneron?

Regeneron has a long history in genetics-based science and has delivered new medicines to patients that were developed based on human genetics discoveries. The Regeneron Genetics Center (RGC) – which we founded in 2014 – is an extension of Regeneron. Aided by unprecedented technological advances, we’ve turned our goal of sequencing hundreds of thousands of individuals for the first time into a reality, enabling us to pursue rare genetic mutations that shine a light on actionable targets and pathways.

The RGC has been successfully applying large-scale human genetics to discover new drug targets, validate existing development programs and identify pharmacogenetic markers. We have collaborated with over 60 institutions around the world representing some of the most valuable cohorts for genetic discovery and have already sequenced more than a quarter million exomes.

Why is it a good time to invest in large initiatives in human genetics research?

There has never been a better time to invest in large initiatives in human genetics research. The successes of the first era of the human genome revolution created a great foundation for today’s discoveries. Technology development has enabled unprecedented scale and the ability to link genomic data to high-quality clinical data. The current era of genomic discovery has tremendous potential and will fuel the next wave of great scientific and medical advances.

Can the RGC sequence all these exomes on their own or are you collaborating with others to tackle this project?

In January, we announced the formation of a major ‘pre-competitive’ consortium to fund the generation of genetic exome sequence data from the 500,000 volunteer participants who make up the UK Biobank health resource. The consortium involves leading life science companies including AbbVie, Alnylam Pharmaceuticals, AstraZeneca, Biogen and Pfizer. Working together will help us speed up the timeline for sequencing the exomes and will give the consortium members a short window of exclusivity before the data goes public. In the end, we’ll be able to share fascinating data with the public faster because of this consortium.

Where do you get your data?

We need access to a whole lot of electronic health records (EHRs). We accomplish this through incredibly successful partnerships with organizations like Geisinger Health System and the UK Biobank. As part20 of our collaboration with Geisinger and UK Biobank, they provide us access to their biobanks and EHRs, we then sequence and analyze the data, and share our findings back with the organisations. This last step is especially exciting because we can help impact patient care when genetic results are handed back to the patient.

Have you started to leverage some of the data you have generated and identified new potential and interesting variants or new drug targets?

The RGC has been successful for Regeneron delivering results and discoveries that advance our science and drug development pipeline. We have fully integrated human genetics into every function and in the evaluation of every target and therapeutic. It has become an essential component of how we conduct our everyday R&D activities. We have advanced dozens of genes from our genetics discoveries into early stages of research and target evaluation. We have identified numerous targets in many diseases, including our most recent discovery of the first genetic variant linked to protection against chronic liver disease, HSD17B13 (see The New England Journal of Medicine).

We also ask questions about existing targets and development programs, enabling us to provide important new insights guiding our development strategy. For instance, we reported that we have identified loss of function mutations in the ANGPTL3 gene (the target of one of our late-stage antibodies) that confer protection from coronary heart disease. Similarly, a 2016 publication of ours highlighted the discovery that inactivating mutations of the ANGPTL4 gene are associated with a significantly reduced risk of coronary heart disease; these same mutations also reduce the risk of diabetes. Many of our findings are already being used to inform Regeneron’s R&D programs, with the ultimate goal of developing treatments for patients in need. There’s much more to come.

Where do you see the biggest challenges in extracting valuable knowledge from large genetics research initiatives?

Challenges and opportunities present themselves in these areas with large-scale genetics initiatives. One of the major challenges is securing high-quality phenotypic data, which is paramount in understanding the effects of genetic mutations on disease. Further, large sample sizes are needed to detect and replicate these effects for rare genetic mutations, where many of the most informative genetic mutations occur.

There are significant informatics and computational challenges related to handling and analyzing large datasets as well as interpreting many of the millions of genetic mutations that we observe. Advances in these fields will be critical to unlocking future genomic discoveries. Perhaps most importantly, we believe that these genetics initiatives must be fully integrated with capabilities for biological and clinical validation to truly extend genetics research discoveries into translational opportunities that impact patients and human health.


Dr Baras
 is Vice President and Head of the Regeneron Genetics Center, a fully integrated program spanning large-scale sequencing, analysis, and translational capabilities facilitating the advancement of Regeneron’s pipeline of therapeutics.

 

Dr Baris will be speaking at The Precision Medicine & Biomarkers Leaders Summit: Europe on ‘Large Scale Human Genetics at Regeneron’. Download the agenda for the full list of speakers. 

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