ArticleAmerican journal of human genetics2023
Development of an oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia.
Article in American journal of human genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 16 citations in OpenAlex.
- Review
- 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
- Depleting prion protein using splice-switching small molecules.bioRxiv : the preprint server for biology · 2026Article
- Exploratory Analysis of ELP1 Expression in Whole Blood From Patients With Familial Dysautonomia.Annals of clinical and translational neurology · 2026Article
- Exon-targeted U1 snRNA rescues splicing defects and ameliorates inherited optic neuropathy: A novel RNA-based treatment.Molecular therapy. Nucleic acids · 2026Article
- AAV2-mediated intravitreal delivery of exon-specific U1 snRNA rescues optic neuropathy in familial dysautonomia.Molecular therapy. Nucleic acids · 2026Article
- Engineered CRISPR-Base Editors as a Permanent Treatment for Familial Dysautonomia.bioRxiv : the preprint server for biology · 2024Article
- Transcriptome analysis in a humanized mouse model of familial dysautonomia reveals tissue-specific gene expression disruption in the peripheral nervous system.Scientific reports · 2024Article
- Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators.Scientific reports · 2023Article
- Familial dysautonomia.Clinical autonomic research : official journal of the Clinical Autonomic Research Society · 2023Review
Corrections and comments
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Authors and funding
21 authors at 4 institutions in 1 country.
Funding
Abstract
Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a splicing mutation in elongator acetyltransferase complex subunit 1 (ELP1). This mutation leads to the skipping of exon 20 and a tissue-specific reduction of ELP1, mainly in the central and peripheral nervous systems. FD is a complex neurological disorder accompanied by severe gait ataxia and retinal degeneration. There is currently no effective treatment to restore ELP1 production in individuals with FD, and the disease is ultimately fatal. After identifying kinetin as a small molecule able to correct the ELP1 splicing defect, we worked on its optimization to generate novel splicing modulator compounds (SMCs) that can be used in individuals with FD. Here, we optimize the potency, efficacy, and bio-distribution of second-generation kinetin derivatives to develop an oral treatment for FD that can efficiently pass the blood-brain barrier and correct the ELP1 splicing defect in the nervous system. We demonstrate that the novel compound PTC258 efficiently restores correct ELP1 splicing in mouse tissues, including brain, and most importantly, prevents the progressive neuronal degeneration that is characteristic of FD. Postnatal oral administration of PTC258 to the phenotypic mouse model TgFD9;Elp1
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