title: Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success.
abstract: Mutations in RPE65, a gene essential to normal operation of the visual (retinoid) cycle, cause the childhood blindness known as Leber congenital amaurosis (LCA). Retinal gene therapy restores vision to blind canine and murine models of LCA. Gene therapy in blind humans with LCA from RPE65 mutations may also have potential for success but only if the retinal photoreceptor layer is intact, as in the early-disease stage-treated animals. Here, we use high-resolution in vivo microscopy to quantify photoreceptor layer thickness in the human disease to define the relationship of retinal structure to vision and determine the potential for gene therapy success. The normally cone photoreceptor-rich central retina and rod-rich regions were studied. Despite severely reduced cone vision, many RPE65-mutant retinas had near-normal central microstructure. Absent rod vision was associated with a detectable but thinned photoreceptor layer. We asked whether abnormally thinned RPE65-mutant retina with photoreceptor loss would respond to treatment. Gene therapy in Rpe65(-/-) mice at advanced-disease stages, a more faithful mimic of the humans we studied, showed success but only in animals with better-preserved photoreceptor structure. The results indicate that identifying and then targeting retinal locations with retained photoreceptors will be a prerequisite for successful gene therapy in humans with RPE65 mutations and in other retinal degenerative disorders now moving from proof-of-concept studies toward clinical trials.
authors.affiliation: Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USA. jacobsos@mail.med.upenn.edu
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: Tomas S
authors.initials: TS
authors.lastname: Aleman
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.forename: Alexander
authors.initials: A
authors.lastname: Sumaroka
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Schwartz
authors.forename: Elizabeth A M
authors.initials: EA
authors.lastname: Windsor
authors.forename: Elias I
authors.initials: EI
authors.lastname: Traboulsi
authors.forename: Elise
authors.initials: E
authors.lastname: Heon
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Pittler
authors.forename: Ann H
authors.initials: AH
authors.lastname: Milam
authors.forename: Albert M
authors.initials: AM
authors.lastname: Maguire
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.forename: Jean
authors.initials: J
authors.lastname: Bennett
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001766:Blindness / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy; D002352:Carrier Proteins; D002648:Child; D003624:Darkness; D005136:Eye Proteins / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation; D010786:Photoreceptor Cells / Q000502:physiology*; D010857:Pigment Epithelium of Eye; D011506:Proteins / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000235:genetics; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
chemical_list: D002352:Carrier Proteins; D005136:Eye Proteins; D011506:Proteins; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase