Approved Research

Analysis of large-scale genotype and phenotype data to facilitate the discovery and development of base editing therapeutics

Lay summary

By far, the largest class of disease-causing mutations involves changes to single DNA base pairs. Most diseases caused by single base pair changes cannot currently be treated with traditional therapeutics, such as small molecule drugs. Thus, developing therapeutics to directly correct disease-causing mutations is of great interest for the treatment of genetic diseases. Recently developed gene-editing technologies, such as base editing, can directly create base substitutions in cellular DNA and therefore safely and efficiently reverse the effect of pathogenic mutations. However, because there are thousands of diseases caused by single base pair changes, it is important to be able to prioritize specific diseases that have the greatest unmet need and which are most likely to be successfully targeted by gene editing approaches. This research aims to use the UK Biobank to inform these decisions. We expect results of this application to include: 1) the discovery of new mutations and genes associated with disease risk; 2) improved understanding of penetrance and clinical presentation of carriers with known disease-causing mutations; and 3) improved understanding of the safety of gene editing therapeutics. This research will advance the development of a new class of therapeutics (base editors), ultimately benefiting patients and contributing to our understanding of the consequences of genetic variation on disease.