title: Replacement gene therapy with a human RPGRIP1 sequence slows photoreceptor degeneration in a murine model of Leber congenital amaurosis.
abstract: RPGR-interacting protein-1 (RPGRIP1) is localized in the photoreceptor-connecting cilium, where it anchors the RPGR (retinitis pigmentosa GTPase regulator) protein, and its function is essential for photoreceptor maintenance. Genetic defect in RPGRIP1 is a known cause of Leber congenital amaurosis (LCA), a severe, early-onset form of retinal degeneration. We evaluated the efficacy of replacement gene therapy in a murine model of LCA carrying a targeted disruption of RPGRIP1. The replacement construct, packaged in an adeno-associated virus serotype 8 (AAV8) vector, used a rhodopsin kinase gene promoter to drive RPGRIP1 expression. Both promoter and transgene were of human origin. After subretinal delivery of the replacement gene in the mutant mice, human RPGRIP1 was expressed specifically in photoreceptors, localized correctly in the connecting cilia, and restored the normal localization of RPGR. Electroretinogram and histological examinations showed better preservation of rod and cone photoreceptor function and improved photoreceptor survival in the treated eyes. This study demonstrates the efficacy of human gene replacement therapy and validates a gene therapy design for future clinical trials in patients afflicted with this condition. Our results also have therapeutic implications for other forms of retinal degenerations attributable to a ciliary defect.
authors.affiliation: Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, and Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.
authors.forename: Basil S
authors.initials: BS
authors.lastname: Pawlyk
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Bulgakov
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Liu
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Xu
authors.forename: Michael
authors.initials: M
authors.lastname: Adamian
authors.forename: Xun
authors.initials: X
authors.lastname: Sun
authors.forename: Shahrokh C
authors.initials: SC
authors.lastname: Khani
authors.forename: Eliot L
authors.initials: EL
authors.lastname: Berson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Sandberg
authors.forename: Tiansen
authors.initials: T
authors.lastname: Li
mesh_terms: D000818:Animals; D003598:Cytoskeletal Proteins; D004195:Disease Models, Animal; D004596:Electroretinography; D051606:G-Protein-Coupled Receptor Kinase 1 / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D055212:Photoreceptor Connecting Cilium / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics* / Q000627:therapeutic use; D012162:Retinal Degeneration / Q000235:genetics / Q000628:therapy
chemical_list: D003598:Cytoskeletal Proteins; D011506:Proteins; C415903:RPGRIP1 protein, human; D051606:G-Protein-Coupled Receptor Kinase 1
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