title: Gene therapy regenerates protein expression in cone photoreceptors in Rpe65(R91W/R91W) mice.
abstract: Cone photoreceptors mediate visual acuity under daylight conditions, so loss of cone-mediated central vision of course dramatically affects the quality of life of patients suffering from retinal degeneration. Therefore, promoting cone survival has become the goal of many ocular therapies and defining the stage of degeneration that still allows cell rescue is of prime importance. Using the Rpe65(R91W/R91W) mouse, which carries a mutation in the Rpe65 gene leading to progressive photoreceptor degeneration in both patients and mice, we defined stages of retinal degeneration that still allow cone rescue. We evaluated the therapeutic window within which cones can be rescued, using a subretinal injection of a lentiviral vector driving expression of RPE65 in the Rpe65(R91W/R91W) mice. Surprisingly, when applied to adult mice (1 month) this treatment not only stalls or slows cone degeneration but, actually, induces cone-specific protein expression that was previously absent. Before the intervention only part of the cones (40% of the number found in wild-type animals) in the Rpe65(R91W/R91W) mice expressed cone transducin (GNAT2); this fraction increased to 64% after treatment. Correct S-opsin localization is also recovered in the transduced region. In consequence these results represent an extended therapeutic window compared to the Rpe65(-/-) mice, implying that patients suffering from missense mutations might also benefit from a prolonged therapeutic window. Moreover, cones are not only rescued during the course of the degeneration, but can actually recover their initial status, meaning that a proportion of altered cones in chromophore deficiency-related disease can be rehabilitated even though they are severely affected.
authors.affiliation: Unit of Gene Therapy and Stem Cell Biology, Jules-Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland. corinne.kostic@fa2.ch
authors.forename: Corinne
authors.initials: C
authors.lastname: Kostic
authors.forename: Sylvain Vincent
authors.initials: SV
authors.lastname: Crippa
authors.forename: Vérène
authors.initials: V
authors.lastname: Pignat
authors.forename: Alexis-Pierre
authors.initials: AP
authors.lastname: Bemelmans
authors.forename: Marijana
authors.initials: M
authors.lastname: Samardzija
authors.forename: Christian
authors.initials: C
authors.lastname: Grimm
authors.forename: Andreas
authors.initials: A
authors.lastname: Wenzel
authors.forename: Yvan
authors.initials: Y
authors.lastname: Arsenijevic
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001120:Arginine / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D006720:Homozygote; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000502:physiology; D020125:Mutation, Missense / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism*; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D014364:Tryptophan / Q000235:genetics; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
chemical_list: D001120:Arginine; D002352:Carrier Proteins; D005136:Eye Proteins; D050505:Mutant Proteins; D011506:Proteins; D014364:Tryptophan; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase