A framework for individualized splice-switching oligonucleotide therapy
Jin‐Kuk Kim, Sijae Woo, Claudio M. de Gusmão, Boxun Zhao, Diana Chin, Renata L. DiDonato, Minh Anh Nguyen, Tojo Nakayama, Chunguang April Hu, Aubrie Soucy, Ashley Kuniholm, Jennifer Karlin Thornton, Olivia Riccardi, Danielle A. Friedman, Christelle Moufawad El Achkar, Zane S. Dash, Laura Cornelissen, Carolina Donado, Kamli N. W. Faour, Lynn Wein Bush, Victoria Suslovitch, Claudia Lentucci, Peter J. Park, Eunjung Alice Lee, Al Patterson, Anthony Philippakis, Brad Margus, Charles B. Berde, Timothy W. Yu
Abstract
Abstract Splice-switching antisense oligonucleotides (ASOs) could be used to treat a subset of individuals with genetic diseases 1 , but the systematic identification of such individuals remains a challenge. Here we performed whole-genome sequencing analyses to characterize genetic variation in 235 individuals (from 209 families) with ataxia-telangiectasia, a severely debilitating and life-threatening recessive genetic disorder 2,3 , yielding a complete molecular diagnosis in almost all individuals. We developed a predictive taxonomy to assess the amenability of each individual to splice-switching ASO intervention; 9% and 6% of the individuals had variants that were ‘probably’ or ‘possibly’ amenable to ASO splice modulation, respectively. Most amenable variants were in deep intronic regions that are inaccessible to exon-targeted sequencing. We developed ASOs that successfully rescued mis-splicing and ATM cellular signalling in patient fibroblasts for two recurrent variants. In a pilot clinical study, one of these ASOs was used to treat a child who had been diagnosed with ataxia-telangiectasia soon after birth, and showed good tolerability without serious adverse events for three years. Our study provides a framework for the prospective identification of individuals with genetic diseases who might benefit from a therapeutic approach involving splice-switching ASOs.