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A framework for individualized splice-switching oligonucleotide therapy
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Journal Article
A framework for individualized splice-switching oligonucleotide therapy
2023
Overview
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.
Whole-genome sequencing analyses in a cohort of individuals with ataxia-telangiectasia are used to identify genetic variants that might be amenable to treatment with splice-switching antisense oligonucleotides (ASOs), and develop ASOs with therapeutic potential.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 38/91
/ 42
/ 45
/ 45/23
/ Ataxia
/ Ataxia Telangiectasia - drug therapy
/ Ataxia Telangiectasia - genetics
/ Child
/ Disease
/ Exons
/ Genomes
/ Genomics
/ Humanities and Social Sciences
/ Humans
/ Introns
/ Kinases
/ Oligonucleotides, Antisense - genetics
/ Oligonucleotides, Antisense - pharmacology
/ Oligonucleotides, Antisense - therapeutic use
/ Patients
/ Science
/ Taxonomy
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