Article ; Online: 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
2023 Volume 110, Issue 3, Page(s) 531–547
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 ... ...
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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MeSH term(s) | Mice ; Animals ; Dysautonomia, Familial/genetics ; Kinetin ; Gait Ataxia ; Retinal Degeneration ; Neurodegenerative Diseases ; Administration, Oral |
Chemical Substances | Kinetin (P39Y9652YJ) |
Language | English |
Publishing date | 2023-02-20 |
Publishing country | United States |
Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
ZDB-ID | 219384-x |
ISSN | 1537-6605 ; 0002-9297 |
ISSN (online) | 1537-6605 |
ISSN | 0002-9297 |
DOI | 10.1016/j.ajhg.2023.01.019 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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