2023 OTS Paper of the Year Spotlight: A Framework for Individualized Splice-Switching Oligonucleotide Therapy
Splice-switching antisense oligonucleotides (ASOs) could be used to treat a subset of individuals with genetic diseases, but the systematic identification of such individuals remains a challenge. We performed whole-genome sequencing on 235 individuals with ataxia-telangiectasia, a severe genetic disorder, and developed a predictive taxonomy to assess their suitability for ASO intervention, finding that 9% and 6% of the individuals had variants ‘probably’ or ‘possibly’ amenable to ASO splice modulation, respectively, with most located in deep intronic regions. We developed ASOs that successfully corrected mis-splicing and restored ATM cellular signaling in patient fibroblasts for two recurrent variants. In a pilot clinical study, one of these ASOs was used to treat a child with ataxia-telangiectasia, showing good tolerability without serious adverse events for over three years. Our study provides a framework for identifying individuals with genetic diseases who might benefit from splice-switching ASOs.
