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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Elsevier
2025-09-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253125001714 |
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| author | Pouiré Yameogo Selina Aguilar Thazha P. Prakash Frank Rigo David R. Lynch Jill S. Napierala Marek Napierala |
| author_facet | Pouiré Yameogo Selina Aguilar Thazha P. Prakash Frank Rigo David R. Lynch Jill S. Napierala Marek Napierala |
| author_sort | Pouiré Yameogo |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-cb5be2a948e34acf9e408603c0b7574a |
| institution | DOAJ |
| issn | 2162-2531 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
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| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj-art-cb5be2a948e34acf9e408603c0b7574a2025-08-20T03:12:01ZengElsevierMolecular Therapy: Nucleic Acids2162-25312025-09-0136310261710.1016/j.omtn.2025.102617Antisense oligonucleotide therapy for patients with Friedreich’s ataxia carrying the c.165+5G>C splicing mutationPouiré Yameogo0Selina Aguilar1Thazha P. Prakash2Frank Rigo3David R. Lynch4Jill S. Napierala5Marek Napierala6Department of Neurology, O’Donnell Brain Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USADepartment of Neurology, O’Donnell Brain Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USAIonis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USAIonis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USADepartment of Pediatrics and Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USADepartment of Neurology, O’Donnell Brain Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA; Corresponding author: Jill S. Napierala, Department of Neurology, O’Donnell Brain Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.Department of Neurology, O’Donnell Brain Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA; Corresponding author: Marek Napierala, Department of Neurology, O’Donnell Brain Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.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.http://www.sciencedirect.com/science/article/pii/S2162253125001714MT: Oligonucleotides: Therapies and ApplicationsFriedreich’s ataxiaantisense oligonucleotidesaberrant splicingfrataxin point mutationcompound heterozygous |
| spellingShingle | Pouiré Yameogo Selina Aguilar Thazha P. Prakash Frank Rigo David R. Lynch Jill S. Napierala Marek Napierala Antisense oligonucleotide therapy for patients with Friedreich’s ataxia carrying the c.165+5G>C splicing mutation Molecular Therapy: Nucleic Acids MT: Oligonucleotides: Therapies and Applications Friedreich’s ataxia antisense oligonucleotides aberrant splicing frataxin point mutation compound heterozygous |
| title | Antisense oligonucleotide therapy for patients with Friedreich’s ataxia carrying the c.165+5G>C splicing mutation |
| title_full | Antisense oligonucleotide therapy for patients with Friedreich’s ataxia carrying the c.165+5G>C splicing mutation |
| title_fullStr | Antisense oligonucleotide therapy for patients with Friedreich’s ataxia carrying the c.165+5G>C splicing mutation |
| title_full_unstemmed | Antisense oligonucleotide therapy for patients with Friedreich’s ataxia carrying the c.165+5G>C splicing mutation |
| title_short | Antisense oligonucleotide therapy for patients with Friedreich’s ataxia carrying the c.165+5G>C splicing mutation |
| title_sort | antisense oligonucleotide therapy for patients with friedreich s ataxia carrying the c 165 5g c splicing mutation |
| topic | MT: Oligonucleotides: Therapies and Applications Friedreich’s ataxia antisense oligonucleotides aberrant splicing frataxin point mutation compound heterozygous |
| url | http://www.sciencedirect.com/science/article/pii/S2162253125001714 |
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