Analysis of Exon Skipping Applicability for Dysferlinopathies

Area of Science:

• Genetics and Molecular Biology
• Neuromuscular Disorders
• Therapeutic Development

Background:

• Dysferlinopathies are genetic disorders caused by mutations in the DYSF gene.
• Exon skipping using antisense oligonucleotides (ASOs) is a potential therapeutic strategy.
• Previous analyses have not comprehensively evaluated exon skipping applicability across the patient population.

Purpose of the Study:

• To analyze the applicability of single- and double-exon skipping strategies for pathogenic DYSF variants.
• To identify exon skipping targets with the broadest potential impact for dysferlinopathy patients.
• To guide the prioritization of ASO-based exon skipping therapies.

Main Methods:

• Utilized the UMD-DYSF database to identify pathogenic variants in dysferlinopathy.
• Evaluated single- and double-exon skipping strategies to exclude pathogenic variants while maintaining the open reading frame.
• Calculated the percentage of pathogenic variants addressable by each strategy.

Main Results:

• Identified 61 theoretically applicable exon skipping strategies.
• These strategies have the potential to address 90.0% of reported pathogenic DYSF variants.
• Single-exon skipping could address 44.6%, and double-exon skipping 45.3% of variants.
• Key targets include exons 28/29 (9.0%), 27/28 (6.7%), and 50/51 (5.4%).

Conclusions:

• Numerous ASO-mediated exon skipping strategies are theoretically applicable for dysferlinopathies.
• The identified strategies could significantly increase treatment accessibility.
• Further preclinical and clinical studies are crucial to validate protein functionality and therapeutic efficacy.