title: Evaluation of Dose and Safety of AAV7m8 and AAV8BP2 in the Non-Human Primate Retina.
abstract: Within the next decade, we will see many gene therapy clinical trials for eye diseases, which may lead to treatments for thousands of visually impaired people around the world. To target retinal diseases that affect specific cell types, several recombinant adeno-associated virus (AAV) serotypes have been generated and used successfully in preclinical mouse studies. Because there are numerous anatomic and physiologic differences between the eyes of mice and "men" and because surgical delivery approaches and immunologic responses also differ between these species, this study evaluated the transduction characteristics of two promising new serotypes, AAV7m8 and AAV8BP2, in the retinas of animals that are most similar to those of humans: non-human primates (NHPs). We report that while AAV7m8 efficiently targets a variety of cell types by subretinal injection in NHPs, transduction after intravitreal delivery was mostly restricted to the inner retina at lower doses that did not induce an immune response. AAV8BP2 targets the cone photoreceptors efficiently but bipolar cells inefficiently by subretinal injection. Additionally, transduction by both serotypes in the anterior chamber of the eye and the optic pathway of the brain was observed post-intravitreal delivery. Finally, we assessed immunogenicity, keeping in mind that these AAV capsids may be used in future clinical trials. We found that AAV8BP2 had a better safety profile compared with AAV7m8, even at the highest doses administered. These studies underscore the differences in AAV transduction between mice and primates, highlighting the importance of careful evaluation of therapeutic vectors in NHPs prior to moving to clinical trials.
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Pavitra S
authors.initials: PS
authors.lastname: Ramachandran
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Vivian
authors.initials: V
authors.lastname: Lee
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Zhangyong
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Ji Yun
authors.initials: JY
authors.lastname: Song
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Giulia
authors.initials: G
authors.lastname: Casal
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Therese
authors.initials: T
authors.lastname: Cronin
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Keirnan
authors.initials: K
authors.lastname: Willett
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Rachel
authors.initials: R
authors.lastname: Huckfeldt
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Jessica I W
authors.initials: JI
authors.lastname: Morgan
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Tomas S
authors.initials: TS
authors.lastname: Aleman
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Albert M
authors.initials: AM
authors.lastname: Maguire
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Jean
authors.initials: J
authors.lastname: Bennett
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000145:classification* / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D011323:Primates; D012160:Retina / Q000166:cytology / Q000378:metabolism*; D012162:Retinal Degeneration / Q000235:genetics / Q000628:therapy*
keywords: AAV; animal models; gene therapy; non-human primate; retina