A framework for individualized splice-switching oligonucleotide therapy

Jinkuk Kim (), Sijae Woo, Claudio M. Gusmao, Boxun Zhao, Diana H. Chin, Renata L. DiDonato, Minh A. Nguyen, Tojo Nakayama, Chunguang April Hu, Aubrie Soucy, Ashley Kuniholm, Jennifer Karlin Thornton, Olivia Riccardi, Danielle A. Friedman, Christelle Moufawad El Achkar, Zane Dash, Laura Cornelissen, Carolina Donado, Kamli N. W. Faour, Lynn W. Bush, Victoria Suslovitch, Claudia Lentucci, Peter J. Park, Eunjung Alice Lee, Al Patterson, Anthony A. Philippakis, Brad Margus, Charles B. Berde and Timothy W. Yu ()
Additional contact information
Jinkuk Kim: Korea Advanced Institute of Science and Technology (KAIST)
Sijae Woo: Korea Advanced Institute of Science and Technology (KAIST)
Claudio M. Gusmao: Boston Children’s Hospital
Boxun Zhao: Boston Children’s Hospital
Diana H. Chin: Boston Children’s Hospital
Renata L. DiDonato: Boston Children’s Hospital
Minh A. Nguyen: Boston Children’s Hospital
Tojo Nakayama: Boston Children’s Hospital
Chunguang April Hu: Boston Children’s Hospital
Aubrie Soucy: Boston Children’s Hospital
Ashley Kuniholm: Boston Children’s Hospital
Jennifer Karlin Thornton: Ataxia Telangiectasia Children’s Project
Olivia Riccardi: Boston Children’s Hospital
Danielle A. Friedman: Boston Children’s Hospital
Christelle Moufawad El Achkar: Boston Children’s Hospital
Zane Dash: Boston Children’s Hospital
Laura Cornelissen: Boston Children’s Hospital
Carolina Donado: Boston Children’s Hospital
Kamli N. W. Faour: Boston Children’s Hospital
Lynn W. Bush: Boston Children’s Hospital
Victoria Suslovitch: Boston Children’s Hospital
Claudia Lentucci: Boston Children’s Hospital
Peter J. Park: Harvard Medical School
Eunjung Alice Lee: Boston Children’s Hospital
Al Patterson: Harvard Medical School
Anthony A. Philippakis: Broad Institute of MIT and Harvard
Brad Margus: Ataxia Telangiectasia Children’s Project
Charles B. Berde: Harvard Medical School
Timothy W. Yu: Boston Children’s Hospital

Nature, 2023, vol. 619, issue 7971, 828-836

Abstract: Abstract Splice-switching antisense oligonucleotides (ASOs) could be used to treat a subset of individuals with genetic diseases1, 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 disorder2,3, 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.

Date: 2023
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DOI: 10.1038/s41586-023-06277-0

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