Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-CB-hRS1, a Recombinant Adeno-Associated Virus Vector Expressing Retinoschisin
Autor: | Jonathan Stoddard, Martha Neuringer, Kellie Howard, James N. Ver Hoeve, Jeffrey D. Chulay, Alok K. Sharma, Ewa Budzynski, Peter Sonnentag, Guo-jie Ye, David R. Knop, Trevor J. McGill, Paul E. Miller |
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Rok vydání: | 2015 |
Předmět: |
Male
Biodistribution Intraocular pressure Pathology medicine.medical_specialty Time Factors Retinoschisis T-Lymphocytes Genetic Vectors Gene Expression Antibodies Viral Retina Cell Line chemistry.chemical_compound Clinical Protocols Genes Reporter medicine Animals Humans Tissue Distribution Transgenes Eye Proteins Ganglion cell layer Genetics (clinical) medicine.diagnostic_test business.industry Correction Retinal Dependovirus medicine.disease Immunohistochemistry Virus Shedding Posterior segment of eyeball Disease Models Animal Macaca fascicularis medicine.anatomical_structure chemistry Intravitreal Injections business Electroretinography |
Zdroj: | Human Gene Therapy Clinical Development. 26:165-176 |
ISSN: | 2324-8645 2324-8637 |
Popis: | 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. |
Databáze: | OpenAIRE |
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