A framework for individualized splice-switching oligonucleotide therapy
Nature · 29 authors, 18 centres
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The study developed a framework to identify rare disease patients who might benefit from personalized splice-switching antisense oligonucleotide (ASO) therapy, using ataxia-telangiectasia as a model. It found that 15% of a 235-person cohort had variants potentially treatable with this approach, with a first-in-human trial underway for two variants.
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This study presents a framework for identifying and developing individualized splice-switching oligonucleotide (ASO) therapies for rare genetic diseases, using a cohort of 235 individuals with ataxia-telangiectasia (A-T) as a model. Whole-genome sequencing (WGS) was used to identify variants potentially amenable to ASO-mediated splice correction. The analysis found that 15% of the cohort (35 individuals) had variants classified as probably or possibly ASO-amenable, with 72% of these variants located in deep intronic regions that would be missed by standard sequencing. Small-scale screening successfully rescued mis-splicing for several tested variants in patient cell lines. For two recurrent variants, ASOs were developed that rescued functional ATM protein deficits. A pilot first-in-human investigational trial for one of these variants has been ongoing for 36 months. The framework suggests that treating 70% of the identified individuals might require as few as 5 distinct ASOs. The authors propose that ~15% might be a reasonable estimate for the proportion of individuals with other recessive genetic conditions who have similar ASO-amenable variants. Limitations include the investigational nature of the approach, logistical and regulatory challenges, and the need for further evidence.
