A framework for individualized splice-switching oligonucleotide therapy.

Area of Science:

• Genetics
• Molecular Biology
• Therapeutics

Background:

• Genetic diseases pose challenges for targeted therapies.
• Identifying individuals suitable for splice-switching antisense oligonucleotide (ASO) therapy requires advanced genetic analysis.
• Ataxia-telangiectasia is a severe, life-threatening recessive genetic disorder.

Purpose of the Study:

• To systematically identify individuals with genetic diseases, specifically ataxia-telangiectasia, who are candidates for splice-switching ASO therapy.
• To develop and validate a predictive model for ASO amenability.
• To demonstrate the efficacy and safety of ASOs in preclinical and clinical settings.

Main Methods:

• Whole-genome sequencing of 235 individuals with ataxia-telangiectasia.
• Development of a predictive taxonomy for ASO splice modulation amenability.
• Design and testing of splice-switching ASOs in patient-derived fibroblasts.
• Pilot clinical study of an ASO in a pediatric patient.

Main Results:

• Achieved a near-complete molecular diagnosis for all participants.
• Identified 9% and 6% of individuals with variants 'probably' or 'possibly' amenable to ASO therapy, respectively.
• Developed ASOs that corrected splicing defects and restored ATM signaling in patient cells.
• Demonstrated good tolerability and safety of an ASO in a three-year pilot clinical study.

Conclusions:

• Whole-genome sequencing combined with predictive modeling can identify patients for ASO therapy.
• Deep intronic variants, often missed by other methods, can be targeted by ASOs.
• This study provides a framework for prospective identification of patients benefiting from ASO-based treatments for genetic disorders.