Genomics to identify novel advanced therapeutics (360G-Wellcome-228320_Z_23_Z)

Rare genetic disease effects millions of people across the world, with the diagnosis and treatment of these conditions proving to be a significant challenge. Most rare diseases are genetic in origin, and recent advances in genetic sequencing technology now give greater potential to discover specific genetic causes of disease and design specialised drugs to target them. One class of drugs, called antisense oligonucleotides (ASOs), can be made to target the specific mutation causing a person’s disease. These drugs work best for certain kinds of genetic mutations, particularly mutations that disrupt splicing of mRNA. We will use the 100,000 Genomes Project dataset to search for participants with pathogenic mutations, commencing with a list of 160 candidate genes which cause severe disease. Using SpliceAI and SVRare, we will find participants who are compound heterozygous for pathogenic mutations. We will evaluate whether the splice variant is a good candidate for ASO therapy, and if so work with colleagues from the Institute of Developmental & Regenerative Medicine. This project may result in the diagnosis of participants currently waiting for a diagnosis in the 100,000 genomes project. Further it may result in the diagnosis and treatment of a participant(s) who have an ASO targetable variant.