Antisense oligonucleotide therapy for patients with Friedreich’s ataxia carrying the c.165+5G>C splicing mutation

Antisense oligonucleotide therapy for patients with Friedreich’s ataxia carrying the c.165+5G>C splicing mutation

Friedreich’s ataxia (FRDA) is a multisystem, progressive disease. 96% of patients carry biallelic GAA triplet expansion mutations in intron 1 of the frataxin gene (FXN). The remaining 4% have a pathogenic GAA expansion on one FXN allele and another mutation on the second allele. A point mutation, FX...

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Bibliographic Details
Main Authors: Pouiré Yameogo, Selina Aguilar, Thazha P. Prakash, Frank Rigo, David R. Lynch, Jill S. Napierala, Marek Napierala
Format: Article
Language:English
Published: Elsevier 2025-09-01
Series:Molecular Therapy: Nucleic Acids
Subjects:
MT: Oligonucleotides: Therapies and Applications
Friedreich’s ataxia
antisense oligonucleotides
aberrant splicing
frataxin point mutation
compound heterozygous
Online Access:http://www.sciencedirect.com/science/article/pii/S2162253125001714
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Summary:Friedreich’s ataxia (FRDA) is a multisystem, progressive disease. 96% of patients carry biallelic GAA triplet expansion mutations in intron 1 of the frataxin gene (FXN). The remaining 4% have a pathogenic GAA expansion on one FXN allele and another mutation on the second allele. A point mutation, FXN c.165+5G>C, was identified in intron 1 of a patient with FRDA resulting in a significant decrease of FXN levels. Using patient fibroblasts, we demonstrated that the c.165+5G>C mutation affects canonical splicing of FXN, leading to the generation of an aberrant transcript. A library of antisense oligonucleotides (ASOs) was designed to target potential intronic splicing regulator motifs and tested in patient cells. Selected O-methoxyethyl (MOE)-ASOs increased FXN levels in c.165+5G>C patient cells without affecting FXN splicing in control cells. The leading MOE-ASO increased expression of a miniFXN gene carrying the c.165+5G>C point mutation by splicing repair. To increase efficacy, we simultaneously targeted the GAA-expanded allele in patient cells using a synthetic transcription factor (synthetic transcription elongation factor 1 [Syn-TEF1]). This ASO strategy may be therapeutically feasible for patients with FRDA with other point mutations that cause splicing defects. Success in developing treatments for disorders with only a few known cases will give hope to patients with FRDA carrying these rare point mutations.
ISSN:2162-2531

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