title: Gene therapy with a promoter targeting both rods and cones rescues retinal degeneration caused by AIPL1 mutations.
abstract: Aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) is required for the biosynthesis of photoreceptor phosphodiesterase (PDE). Gene defects in AIPL1 cause a heterogeneous set of conditions ranging from Leber's congenital amaurosis (LCA), the severest form of early-onset retinal degeneration, to milder forms such as retinitis pigmentosa (RP) and cone-rod dystrophy. In mice, null and hypomorphic alleles cause retinal degeneration similar to human LCA and RP, respectively. Thus these mouse models represent two ends of the disease spectrum associated with AIPL1 gene defects in humans. We evaluated whether adeno-associated virus (AAV)-mediated gene replacement therapy in these models could restore PDE biosynthesis in rods and cones and thereby improve photoreceptor survival. We validated the efficacy of human AIPL1 (isoform 1) replacement gene controlled by a promoter derived from the human rhodopsin kinase (RK) gene, which is active in both rods and cones. We found substantial and long-term rescue of the disease phenotype as a result of transgene expression. This is the first gene therapy study in which both rods and cones were targeted successfully with a single photoreceptor-specific promoter. We propose that the vector and construct design used in this study could serve as a prototype for a human clinical trial.
authors.affiliation: Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.
authors.forename: X
authors.initials: X
authors.lastname: Sun
authors.forename: B
authors.initials: B
authors.lastname: Pawlyk
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.forename: O V
authors.initials: OV
authors.lastname: Bulgakov
authors.forename: M
authors.initials: M
authors.lastname: Adamian
authors.forename: M A
authors.initials: MA
authors.lastname: Sandberg
authors.forename: S C
authors.initials: SC
authors.lastname: Khani
authors.forename: M-H
authors.initials: MH
authors.lastname: Tan
authors.forename: A J
authors.initials: AJ
authors.lastname: Smith
authors.forename: R R
authors.initials: RR
authors.lastname: Ali
authors.forename: T
authors.initials: T
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D005136:Eye Proteins; D051606:G-Protein-Coupled Receptor Kinase 1 / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D029242:Optic Atrophy, Hereditary, Leber / Q000628:therapy*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism; D012162:Retinal Degeneration / Q000628:therapy*; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism*
chemical_list: C403625:AIPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D005136:Eye Proteins; D051606:G-Protein-Coupled Receptor Kinase 1; D010727:Phosphoric Diester Hydrolases