Tailored antisense oligonucleotides designed to correct aberrant splicing reveal actionable groups of mutations for rare genetic disorders

Abstract

Effective translation of rare disease diagnosis knowledge into therapeutic applications is achievable within a reasonable timeframe, where mutations are amenable to current antisense oligonucleotide technology. In our study, we identified five distinct types of abnormal splice-causing mutations in patients with rare genetic disorders and developed a tailored antisense oligonucleotide for each mutation type, using phosphorodiamidate morpholino oligomers with or without octa-guanidine dendrimers and 2'-O-methoxyethyl phosphorothioate. We observed variations in treatment effects and efficiencies, influenced by both the chosen chemistry and the specific nature of the aberrant splicing patterns targeted for correction. Our study demonstrates the successful correction of all five different types of aberrant splicing. Our findings reveal that effective correction of aberrant splicing can depend on altering the oligonucleotide's chemical composition and suggests a fast, efficient, and feasible approach to develop personalised therapeutic interventions for genetic disorders in short time frames.

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Identifiers

ORCID for Htoo A. Wai: orcid.org/0000-0002-3560-6980

ORCID for John Holloway: orcid.org/0000-0001-9998-0464

ORCID for Diana Baralle: orcid.org/0000-0003-3217-4833

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