title: Dosage thresholds for AAV2 and AAV8 photoreceptor gene therapy in monkey.
abstract: Gene therapy is emerging as a therapeutic modality for treating disorders of the retina. Photoreceptor cells are the primary cell type affected in many inherited diseases of retinal degeneration. Successfully treating these diseases with gene therapy requires the identification of efficient and safe targeting vectors that can transduce photoreceptor cells. One serotype of adeno-associated virus, AAV2, has been used successfully in clinical trials to treat a form of congenital blindness that requires transduction of the supporting cells of the retina in the retinal pigment epithelium (RPE). Here, we determined the dose required to achieve targeting of AAV2 and AAV8 vectors to photoreceptors in nonhuman primates. Transgene expression in animals injected subretinally with various doses of AAV2 or AAV8 vectors carrying a green fluorescent protein transgene was correlated with surgical, clinical, and immunological observations. Both AAV2 and AAV8 demonstrated efficient transduction of RPE, but AAV8 was markedly better at targeting photoreceptor cells. These preclinical results provide guidance for optimal vector and dose selection in future human gene therapy trials to treat retinal diseases caused by loss of photoreceptors.
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania, and Center for Cellelar and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Luk H
authors.initials: LH
authors.lastname: Vandenberghe
authors.forename: Peter
authors.initials: P
authors.lastname: Bell
authors.forename: Albert M
authors.initials: AM
authors.lastname: Maguire
authors.forename: Cassia N
authors.initials: CN
authors.lastname: Cearley
authors.forename: Ru
authors.initials: R
authors.lastname: Xiao
authors.forename: Roberto
authors.initials: R
authors.lastname: Calcedo
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Castle
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Maguire
authors.forename: Rebecca
authors.initials: R
authors.lastname: Grant
authors.forename: John H
authors.initials: JH
authors.lastname: Wolfe
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
authors.forename: Jean
authors.initials: J
authors.lastname: Bennett
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics* / Q000378:metabolism; D005260:Female; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008251:Macaca; D008297:Male; D010786:Photoreceptor Cells / Q000166:cytology / Q000502:physiology*; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000628:therapy; D014161:Transduction, Genetic; D019076:Transgenes
chemical_list: D049452:Green Fluorescent Proteins