期刊
CELL REPORTS
卷 25, 期 3, 页码 611-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2018.09.043
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类别
资金
- Intramural Research Program of the National Eye Institute [EY000443, EY000474, EY000546]
- National Institute on Deafness and Other Communication Disorders [DC000082-02]
Mutations in CEP290 cause ciliogenesis defects, leading to diverse clinical phenotypes, including Leber congenital amaurosis (LCA). Gene therapy for CEP290-associated diseases is hindered by the 7.4 kb CEP290 coding sequence, which is difficult to deliver in vivo. The multi-domain structure of the CEP290 protein suggests that a specific CEP290 domain may complement disease phenotypes. Thus, we constructed AAV vectors with overlapping CEP290 regions and evaluated their impact on photoreceptor degeneration in Cep290(rd16/rd16 )and cep290(rd16/rd16); Nrl(-/-) mice, two models of CEP290-LCA. One CEP290 fragment (the C-terminal 989 residues, including the domain deleted in mutant mice) reconstituted CEP290 function and resulted in cone preservation and delayed rod death. The CEP290 C-terminal domain also improved cilia phenotypes in mouse embryonic fibroblasts and iPSC-derived retinal organoids carrying the Cep290(rd/6 )mutation. Our study strongly argues for in trans complementation of CEP290 mutations by a cognate fragment and suggests therapeutic avenues.
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