Identification of mis-splicing and antisense oligonucleotide-amenable human variant

Abstract

Rare genetic diseases impact over 400 million patients globally, yet diagnostic and therapeutic unmet needs persist. This thesis analyzed whole genome sequencing data from 235 ataxia-telangiectasia (A-T) patients to enhance genetic diagnosis and systematically assess possibilities for antisense oligonucleotide (ASO) therapies targeting RNA mis-splicing. With an augmented bioinformatics pipeline, 98.7% of A-T patients received a complete genetic diagnosis. Additionally, 15% (35/235) of patients were identified to have at least one ASO-amenable variant. Follow-up experiments confirmed the mis-splicing events and ASO-amenability predicted with computational tools. Advanced ASO development for a prioritized mis-splicing variant in ATM gene enabled launch of an individualized clinical trial to evaluate impact on disease progression. Analysis of two ABCA4-associated retinopathy cohorts revealed consistency in estimated ASO-amenability rates, suggesting potential broader applicability to other rare diseases. Overall this methodology transforms traditional notions of therapy development for ultra-rare diseases. By systematically pinpointing pathogenic variants in rare disease patients and designing variant-targeting ASOs to correct RNA mis-splicing events, rapid translation of personalized medicines based on characteristics of pathogenic variants is made possible. Study innovations in genetic diagnosis, assessment of therapeutic potential, and demonstration of clinical feasibility provide a framework for translating personalized medicine to rare disease patients. Expansion to additional cohorts and diseases along with refinements in analysis algorithms will further meet diagnostic and therapeutic unmet needs in rare diseases.