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Analysis of Exon Skipping Applicability for Dysferlinopathies

Authors: Jamie Leckie; Sebastian Hernandez Rodriguez; Martin Krahn; Toshifumi Yokota;

Analysis of Exon Skipping Applicability for Dysferlinopathies

Abstract

Exon skipping, mediated through antisense oligonucleotides (ASOs), is a promising approach to exclude pathogenic variants from the DYSF gene and treat dysferlinopathies. Understanding the applicability of various exon skipping strategies in the total patient population, an analysis not previously performed, can help guide researchers in prioritizing therapies with the broadest potential impact. Using data from the UMD-DYSF database, we evaluated all reported pathogenic variants in dysferlinopathy patients for the applicability of single- or double-exon skipping approaches to exclude the pathogenic variants while maintaining the open reading frame. A total of 61 theoretically applicable exon skipping strategies were identified, with the potential to address 90.0% of the pathogenic variants reported—44.6% through single-exon skipping and 45.3% through double-exon skipping. The most broadly applicable targets include exons 28 and 29 (9.0%), exons 27 and 28 (6.7%), and exons 50 and 51 (5.4%). While numerous theoretically applicable strategies were identified, it remains unclear if the truncated proteins produced through each exon skipping strategy will have improved functionality to alleviate patient symptoms. Further preclinical studies and clinical trials will be essential to determine the effectiveness of these therapies, potentially expanding access to disease-modifying treatments for dysferlinopathy patients.

Keywords

applicability, QH573-671, [SDV.GEN] Life Sciences [q-bio]/Genetics, antisense oligonucleotide (ASO), Review, Exons, Genetic Therapy, Oligonucleotides, Antisense, dysferlinopathy, Muscular Dystrophies, Limb-Girdle, Humans, Cytology, Dysferlin, exon skipping

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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
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Average
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