title: Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-CB-hRS1, a Recombinant Adeno-Associated Virus Vector Expressing Retinoschisin.
abstract: Applied Genetic Technologies Corporation is developing rAAV2tYF-CB-hRS1, a recombinant adeno-associated virus (rAAV) vector for treatment of X-linked retinoschisis (XLRS), an inherited retinal disease characterized by splitting (schisis) of retinal layers causing poor vision. We report here results of a study evaluating the safety and biodistribution of rAAV2tYF-CB-hRS1 in normal cynomolgus macaques. Three groups of male animals (n = 6 per group) received an intravitreal injection in one eye of either vehicle, or rAAV2tYF-CB-hRS1 at one of two dose levels (4 × 10(10) or 4 × 10(11) vg/eye). Half the animals were sacrificed after 14 days and the others after 91 or 115 days. The intravitreal injection procedure was well tolerated in all groups. Serial ophthalmic examinations demonstrated a dose-related anterior and posterior segment inflammatory response that improved over time. There were no test article-related effects on intraocular pressure, electroretinography, visual evoked potential, hematology, coagulation, clinical chemistry, or gross necropsy observations. Histopathological examination demonstrated minimal or moderate mononuclear infiltrates in 6 of 12 vector-injected eyes. Immunohistochemical staining showed RS1 labeling of the ganglion cell layer at the foveal slope in vector-injected eyes at both dose levels. Serum anti-AAV antibodies were detected in 4 of 6 vector-injected animals at the day 15 sacrifice and all vector-injected animals at later time points. No animals developed antibodies to RS1. Biodistribution studies demonstrated high levels of vector DNA in the injected eye but minimal or no vector DNA in any other tissue. These results support the use of rAAV2tYF-CB-hRS1 in clinical studies in patients with XLRS.
authors.affiliation: 1 Applied Genetic Technologies Corporation , Alachua, Florida.
authors.forename: Guo-Jie
authors.initials: GJ
authors.lastname: Ye
authors.affiliation: 2 Covance Laboratories, Inc. , Madison, Wisconsin.
authors.forename: Ewa
authors.initials: E
authors.lastname: Budzynski
authors.affiliation: 2 Covance Laboratories, Inc. , Madison, Wisconsin.
authors.forename: Peter
authors.initials: P
authors.lastname: Sonnentag
authors.affiliation: 3 OSOD , Madison, Wisconsin.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Miller
authors.affiliation: 2 Covance Laboratories, Inc. , Madison, Wisconsin.
authors.forename: Alok K
authors.initials: AK
authors.lastname: Sharma
authors.affiliation: 3 OSOD , Madison, Wisconsin.
authors.forename: James N
authors.initials: JN
authors.lastname: Ver Hoeve
authors.affiliation: 4 Laboratory Corporation of America® Holdings , Seattle, Washington.
authors.forename: Kellie
authors.initials: K
authors.lastname: Howard
authors.affiliation: 1 Applied Genetic Technologies Corporation , Alachua, Florida.
authors.forename: David R
authors.initials: DR
authors.lastname: Knop
authors.forename: Martha
authors.initials: M
authors.lastname: Neuringer
authors.forename: Trevor
authors.initials: T
authors.lastname: McGill
authors.forename: Jonathan
authors.initials: J
authors.lastname: Stoddard
authors.affiliation: 1 Applied Genetic Technologies Corporation , Alachua, Florida.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Chulay
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D002460:Cell Line; D002985:Clinical Protocols; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics*; D015870:Gene Expression; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics* / Q000493:pharmacokinetics*; D006801:Humans; D007150:Immunohistochemistry; D058449:Intravitreal Injections; D008252:Macaca fascicularis; D008297:Male; D012160:Retina / Q000378:metabolism / Q000473:pathology; D041441:Retinoschisis / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D019076:Transgenes; D017201:Virus Shedding
chemical_list: D000914:Antibodies, Viral; D005136:Eye Proteins; C108726:RS1 protein, human