ArticleNucleic acids research2018
Antisense oligonucleotides correct the familial dysautonomia splicing defect in IKBKAP transgenic mice.
Article in Nucleic acids research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 64 citations in OpenAlex.
- To scramble or not: Steric blocking 2'-MOE/PS control antisense oligonucleotides across cellular models.Molecular therapy. Nucleic acids · 2026Article
- ELP1 gene augmentation restores visual function in a mouse model of familial dysautonomia.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Peripheral neuron phenotypes of familial dysautonomia are rescued by AAV-mediated gene therapy.Clinical autonomic research : official journal of the Clinical Autonomic Research Society · 2026Article
- A novel splice site variant in DEGS1 leads to aberrant splicing and loss of DEGS1 enzyme activity, a VUS resolved.Human genetics · 2026Article
- Exploratory Analysis of ELP1 Expression in Whole Blood From Patients With Familial Dysautonomia.Annals of clinical and translational neurology · 2026Article
- Prime editing of the common Familial Dysautonomia-causing c.2204 + 6T > C splicing mutation.Orphanet journal of rare diseases · 2026Article
- AAV2-mediated intravitreal delivery of exon-specific U1 snRNA rescues optic neuropathy in familial dysautonomia.Molecular therapy. Nucleic acids · 2026Article
- Peripheral neuron phenotypes of familial dysautonomia are rescued by AAV-mediated gene therapy.Research square · 2025Article
- A Manual for Genome and Transcriptome Engineering.IEEE reviews in biomedical engineering · 2025Review
- Engineered CRISPR-Base Editors as a Permanent Treatment for Familial Dysautonomia.bioRxiv : the preprint server for biology · 2024Article
- Genipin rescues developmental and degenerative defects in familial dysautonomia models and accelerates axon regeneration.Science translational medicine · 2024Article
- Specificity, synergy, and mechanisms of splice-modifying drugs.Nature communications · 2024Article
- Linking the Extended Autonomic System with the Homeostat Theory: New Perspectives about Dysautonomias.Journal of personalized medicine · 2024Article
- Age-dependent regulation of ELP1 exon 20 splicing in Familial Dysautonomia by RNA Polymerase II kinetics and chromatin structure.PloS one · 2024Article
- Familial dysautonomia.Clinical autonomic research : official journal of the Clinical Autonomic Research Society · 2023Review
- Regulation of pre-mRNA splicing: roles in physiology and disease, and therapeutic prospects.Nature reviews. Genetics · 2023Review
- Development of an oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia.American journal of human genetics · 2023Article
- Delivering the Promise of Gene Therapy with Nanomedicines in Treating Central Nervous System Diseases.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Review
- Rescue of a familial dysautonomia mouse model by AAV9-Exon-specific U1 snRNA.American journal of human genetics · 2022Article
- Genetic pain loss disorders.Nature reviews. Disease primers · 2022Review
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 3 countries.
Funding
Abstract
Familial dysautonomia (FD) is a rare inherited neurodegenerative disorder caused by a point mutation in the IKBKAP gene that results in defective splicing of its pre-mRNA. The mutation weakens the 5' splice site of exon 20, causing this exon to be skipped, thereby introducing a premature termination codon. Though detailed FD pathogenesis mechanisms are not yet clear, correcting the splicing defect in the relevant tissue(s), thus restoring normal expression levels of the full-length IKAP protein, could be therapeutic. Splice-switching antisense oligonucleotides (ASOs) can be effective targeted therapeutics for neurodegenerative diseases, such as nusinersen (Spinraza), an approved drug for spinal muscular atrophy. Using a two-step screen with ASOs targeting IKBKAP exon 20 or the adjoining intronic regions, we identified a lead ASO that fully restored exon 20 splicing in FD patient fibroblasts. We also characterized the corresponding cis-acting regulatory sequences that control exon 20 splicing. When administered into a transgenic FD mouse model, the lead ASO promoted expression of full-length human IKBKAP mRNA and IKAP protein levels in several tissues tested, including the central nervous system. These findings provide insights into the mechanisms of IKBKAP exon 20 recognition, and pre-clinical proof of concept for an ASO-based targeted therapy for FD.
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