Targeting UTR regulation as a gene-level therapeutic strategy for rare disease (360G-Wellcome-305292_Z_23_Z)

Rare disorders are a major cause of mortality and morbidity and collectively affect over 300 million people worldwide. The UK is a world leader in genetic diagnosis, with the NHS providing routine genome sequencing, however, effective treatments do not exist for most individuals. Recent advances in genome-editing and nucleic acid therapies empower the development of effective patient-personalised therapies. A particularly powerful class of emerging therapies act by modulating gene regulation and circumvent the need to design separate therapies for each specific variant in a gene. Development of these gene-level therapies requires an in-depth knowledge of the regulation of individual disease genes. Untranslated regions (UTRs) are key gene regulatory elements with enormous but untapped therapeutic potential. Here, through large-scale data integration, I will generate a deep understanding of UTR- mediated gene regulation. I will use this to uncover novel disease biology, improve rare disease diagnosis, and ultimately determine which genes and patients are treatable with nucleic acid and genome editing therapies that target UTR-mediated gene regulation. I will prioritise targets for functional validation and licence successful targets to bring them to patients. Finally, I will create an open resource of therapeutically tractable genes to empower therapeutic development for rare disorders at scale.