title: Retinal degeneration progression changes lentiviral vector cell targeting in the retina.
abstract: In normal mice, the lentiviral vector (LV) is very efficient to target the RPE cells, but transduces retinal neurons well only during development. In the present study, the tropism of LV has been investigated in the degenerating retina of mice, knowing that the retina structure changes during degeneration. We postulated that the viral transduction would be increased by the alteration of the outer limiting membrane (OLM). Two different LV pseudotypes were tested using the VSVG and the Mokola envelopes, as well as two animal models of retinal degeneration: light-damaged Balb-C and Rhodopsin knockout (Rho-/-) mice. After light damage, the OLM is altered and no significant increase of the number of transduced photoreceptors can be obtained with a LV-VSVG-Rhop-GFP vector. In the Rho-/- mice, an alteration of the OLM was also observed, but the possibility of transducing photoreceptors was decreased, probably by ongoing gliosis. The use of a ubiquitous promoter allows better photoreceptor transduction, suggesting that photoreceptor-specific promoter activity changes during late stages of photoreceptor degeneration. However, the number of targeted photoreceptors remains low. In contrast, LV pseudotyped with the Mokola envelope allows a wide dispersion of the vector into the retina (corresponding to the injection bleb) with preferential targeting of Müller cells, a situation which does not occur in the wild-type retina. Mokola-pseudotyped lentiviral vectors may serve to engineer these glial cells to deliver secreted therapeutic factors to a diseased area of the retina.
authors: Unit of Gene Therapy and Stem Cell Biology, Service of Ophthalmology, Jules-Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland.
authors: Maritza
authors: M
authors: Calame
authors: Maité
authors: M
authors: Cachafeiro
authors: Stéphanie
authors: S
authors: Philippe
authors: Karine
authors: K
authors: Schouwey
authors: Meriem
authors: M
authors: Tekaya
authors: Dana
authors: D
authors: Wanner
authors: Chamsy
authors: C
authors: Sarkis
authors: Corinne
authors: C
authors: Kostic
authors: Yvan
authors: Y
authors: Arsenijevic
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics*; D005911:Gliosis / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics; D012160:Retina / Q000378:metabolism* / Q000473:pathology*; D012162:Retinal Degeneration / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D014161:Transduction, Genetic; D019745:cis-trans-Isomerases; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000099178:Retinoid Isomerohydrolase
chemical_list: D002352:Carrier Proteins; D005136:Eye Proteins; D019745:cis-trans-Isomerases; D020741:rho GTP-Binding Proteins; D000099178:Retinoid Isomerohydrolase