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Cell Rep. 2018 Oct 16;25(3):611-623.e6. doi: 10.1016/j.celrep.2018.09.043.

A CEP290 C-Terminal Domain Complements the Mutant CEP290 of Rd16 Mice In Trans and Rescues Retinal Degeneration.

Author information

1
Ocular Gene Therapy Core, National Eye Institute, NIH, Bethesda, MD 20892, USA.
2
Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH, Bethesda, MD 20892, USA.
3
Neurotology Program, National Institute on Deafness and Communication Disorders, NIH, Bethesda, MD 20892, USA.
4
Ocular Gene Therapy Core, National Eye Institute, NIH, Bethesda, MD 20892, USA. Electronic address: wuzh@mail.nih.gov.

Abstract

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 Cep290rd16/rd16 and Cep290rd16/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 Cep290rd16 mutation. Our study strongly argues for in trans complementation of CEP290 mutations by a cognate fragment and suggests therapeutic avenues.

KEYWORDS:

AAV; CEP290; LCA; ciliopathy; gene therapy; photoreceptors; retinal degeneration

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