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Cited by 41Retinal Development and DisordersGenetic and Kidney Cyst DiseasesVirus-based gene therapy research

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

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Mookherjee, Suddhasil, Chen, Holly Yu, Isgrig, Kevin, Yu, Wenhan, Hiriyanna, Suja, Levron, Rivka, Li, Tiansen, Colosi, Peter +3 more·2018·Cell Reports
DOI 10.1016/j.celrep.2018.09.043PMC PMC6245950
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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 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 rd16 mutation. Our study strongly argues for in trans complementation of CEP290 mutations by a cognate fragment and suggests therapeutic avenues.

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  • Another study reported that the Cep290 rd16 mutation could be complemented in trans by a C-terminal CEP290 fragment delivered via AAV8-subretinal injection, which improved visual behavior in test mice.

    “Another study has favored a 'transcomplementation' strategy, reporting that the Cep290 rd16 mutation could be complemented in trans by a C-terminal CEP290 fragment delivered via AAV8-subretinal injection, which improved visual behavior in test mice [105].”

    From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [105]

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Cited by

Sorted by citations

Authors
Mookherjee, S., Chen, H. Y., Isgrig, K., Yu, W., Hiriyanna, S., Levron, R., Li, T., Colosi, P., Chien, W., Swaroop, A., & Wu, Z.
Affiliations
National Institutes of Health (US)
Corresponding author
Wu, Zhijian
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2018-10
Volume
25
Issue
3
Pages
611-623.e6
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2018.09.043
PMC
PMC6245950
OpenAlex
W2896560552
Cited by
41
References
3
Citations by year
2025: 3 · 2024: 3 · 2023: 9 · 2022: 4 · 2021: 7 · 2020: 5 · 2019: 9
FWCI
1.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Intramural Research Program of the National Eye Institute (EY000443, EY000474, EY000546)
  • National Institute on Deafness and Other Communication Disorders (DC000082-02)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Keywords
CEP290, Leber congenital amaurosis, retinal degeneration, C-terminal domain, adeno-associated virus vectors, gene therapy, photoreceptor degeneration, retinal organoids, mouse embryonic fibroblasts
MeSH terms
Dependovirus, Animals, Antigens, Neoplasm, Cilia, Cytoskeletal Proteins, Disease Models, Animal, Eye Proteins, Female, Humans, Male, Mutation, Retina, Retinal Degeneration, Genetic Therapy, Retinal Cone Photoreceptor Cells, Mice, Knockout, Cell Cycle Proteins, Basic-Leucine Zipper Transcription Factors, Mice, Leber Congenital Amaurosis

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