Genomics-Driven Drug Discovery: AstraZeneca CNV Study, Helix Deal, Quotient Platform

AstraZeneca has published a large-scale analysis of copy number variants (CNVs) in more than 470,000 individuals in Nature, one of the largest studies of its kind, and has entered a multiyear agreement with Helix for access to clinico-genomic data for drug discovery. Separately, Quotient Therapeutics is advancing a somatic genomics platform aimed at uncovering disease-driving mutations.

The latest research, published in Nature, characterizes large DNA deletions or duplications—called copy number variants (CNVs)—to create one of the largest CNV analyses to date. The results are openly accessible through the AZPheWAS portal. According to AstraZeneca, therapeutic targets with human genetic insights are up to seven times more likely to be approved as medicines. When a region is duplicated, a gene could produce too much protein, which may contribute to disease; when a region is deleted, less protein is made. In some cases, insufficient protein levels may lower disease risk, revealing natural protective mechanisms referred to as genetic resilience. The multi-ancestry analysis identified a duplication involving the HNF1B gene that is associated with higher levels of the HNF1B protein and an increased likelihood of developing chronic kidney disease. It also found that an IGHE gene deletion significantly lowers IgE levels and offers natural protection against developing asthma and allergic disease.

In a separate development, Helix said it has inked a multiyear agreement with AstraZeneca, giving the pharma giant access to its GenoSphere research cohorts, including enhanced exome and longitudinal clinical data, for drug discovery and development. Financial terms were not disclosed. Helix's database includes electronic health records covering an average of 13 years per patient, clinical exome and whole-genome backbone data, and third-party medical, pharmacy, and mortality claims. Participants are fully consented and can be approached for follow-on studies. Helix forged similar deals with GlaxoSmithKline this year and with Alnylam last year.

Quotient Therapeutics is developing a somatic genomics platform that combines highly accurate genome sequencing with computational analysis to identify somatic mutations and translate them into drug targets. Somatic mutations accumulate as cells divide and respond to environmental exposures, creating genetic variation across tissues. Mutation rates are constant over time: a blood cell in a 60-year-old person will have twice as many mutations as one from a 30-year-old. An adult has about 10 billion T lymphocyte clones, and by age 60 they have, on average, 2,000 mutations per cell, equating to 10,000 mutations generated in T lymphocytes every second. By age 60, every one of the 3 billion bases in the genome is mutated 6,000 times on average. Somatic mutations also play a causal role in the biology of many diseases beyond cancer, with some mutations protecting cells against disease processes and others driving disease; Quotient aims to develop drugs that mimic protective mutations or reverse the effects of disease-driving mutations.