title: Assessment of tropism and effectiveness of new primate-derived hybrid recombinant AAV serotypes in the mouse and primate retina.
abstract: Adeno-associated viral vectors (AAV) have been shown to be safe in the treatment of retinal degenerations in clinical trials. Thus, improving the efficiency of viral gene delivery has become increasingly important to increase the success of clinical trials. In this study, structural domains of different rAAV serotypes isolated from primate brain were combined to create novel hybrid recombinant AAV serotypes, rAAV2/rec2 and rAAV2/rec3. The efficacy of these novel serotypes were assessed in wild type mice and in two models of retinal degeneration (the Abca4(-/-) mouse which is a model for Stargardt disease and in the Pde6b(rd1/rd1) mouse) in vivo, in primate tissue ex-vivo, and in the human-derived SH-SY5Y cell line, using an identical AAV2 expression cassette. We show that these novel hybrid serotypes can transduce retinal tissue in mice and primates efficiently, although no more than AAV2/2 and rAAV2/5 serotypes. Transduction efficiency appeared lower in the Abca4(-/-) mouse compared to wild type with all vectors tested, suggesting an effect of specific retinal diseases on the efficiency of gene delivery. Shuffling of AAV capsid domains may have clinical applications for patients who develop T-cell immune responses following AAV gene therapy, as specific peptide antigen sequences could be substituted using this technique prior to vector re-treatments.
authors.affiliation: Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Charbel Issa
authors.forename: Samantha R
authors.initials: SR
authors.lastname: De Silva
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Lipinski
authors.forename: Mandeep S
authors.initials: MS
authors.lastname: Singh
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mouravlev
authors.forename: Qisheng
authors.initials: Q
authors.lastname: You
authors.forename: Alun R
authors.initials: AR
authors.lastname: Barnard
authors.forename: Mark W
authors.initials: MW
authors.lastname: Hankins
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: During
authors.forename: Robert E
authors.initials: RE
authors.lastname: Maclaren
mesh_terms: D000818:Animals; D002460:Cell Line; D000229:Dependovirus / Q000145:classification / Q000502:physiology*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011323:Primates; D011995:Recombination, Genetic; D012160:Retina / Q000378:metabolism* / Q000821:virology; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D056189:Viral Tropism
chemical_list: D049452:Green Fluorescent Proteins