1. Gene Therapy Using a miniCEP290 Fragment Delays Photoreceptor Degeneration in a Mouse Model of Leber Congenital Amaurosis
- Author
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Hemant Khanna, Linjing Li, Guangping Gao, Wei Zhang, and Qin Su
- Subjects
0301 basic medicine ,Retinal degeneration ,retina ,Genetic enhancement ,Genetic Vectors ,Leber Congenital Amaurosis ,Cell Cycle Proteins ,030105 genetics & heredity ,Biology ,medicine.disease_cause ,Virus ,Mice ,03 medical and health sciences ,Antigens, Neoplasm ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Gene ,Research Articles ,Cells, Cultured ,Mutation ,Retina ,Gene therapy of the human retina ,LCA ,Cilium ,cilia ,Genetic Therapy ,Dependovirus ,medicine.disease ,photoreceptor ,gene therapy ,Neoplasm Proteins ,3. Good health ,Cell biology ,Cytoskeletal Proteins ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Molecular Medicine ,ciliopathies - Abstract
Mutations in the cilia-centrosomal protein CEP290 are frequently observed in autosomal recessive childhood blindness disorder Leber congenital amaurosis (LCA). No treatment or cure currently exists for this disorder. The Cep290rd16 (retinal degeneration 16) mouse (a model of LCA) carries a mutation in the Cep290 gene. This mutation leads to shorter cilia formation and defective photoreceptor structure and function. A roadblock to developing a gene replacement strategy for CEP290 using conventional adeno-associated virus (AAV) vectors is its large size. The identification and characterization is reported of a miniCEP290 gene that is amenable to AAV2/8-mediated delivery and delaying retinal degeneration in the Cep290rd16 mice. Using the ability of Cep290rd16 mouse embryonic fibroblasts to from shorter cilia as a platform, a human CEP290 domain encoded by amino acids 580–1180 (miniCEP290580-1180) was identified that can recover the cilia length in vitro. Furthermore, subretinal injection of AAV particles carrying the cDNA expressing miniCEP290580-1180 into neonatal Cep290rd16 mice resulted in significantly improved photoreceptor survival, morphology, and function compared to control injected mice. These studies show the potential of using a truncated CEP290 to treat this fast progressing and devastating disease.
- Published
- 2018