Preclinical safety evaluation of subretinal AAV2.sFlt-1 in non-human primates

• Published in: Gene therapy Vol. 19; no. 10; pp. 999 - 1009
• Main Authors: LAI, C.-M, ESTCOURT, M. J, ANG, C.-L, DER MOST, Rg Van, CONSTABLE, I. J, DISMUKE, D, SAMULSKI, R. J, DEGLI-ESPOSTI, M. A, RAKOCZY, E. P, HIMBECK, R. P, LEE, S.-Y, YEO, I. Yew-San, LUU, C, LOH, B. K, LEE, M. W, BARATHI, A, VILLANO, J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.10.2012
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Anterior chamber; Applied cell therapy and gene therapy; Biological and medical sciences; Biotechnology; Care and treatment; Cell-mediated immunity; Complications and side effects; Dependovirus - genetics; Diabetes; Eye; Eye diseases; Fundamental and applied biological sciences. Psychology; Gene therapy; Genetic aspects; Genetic Therapy - adverse effects; Genetic Vectors; Health aspects; Health. Pharmaceutical industry; Immunology; Indexing in process; Industrial applications and implications. Economical aspects; Injection; Macaca fascicularis; Macular degeneration; Medical sciences; Neovascularization; Physiological aspects; Retina - immunology; Retina - metabolism; Retinal Neovascularization - genetics; Retinal Neovascularization - immunology; Retinal Neovascularization - therapy; Risk factors; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Vascular endothelial growth factor; Vascular Endothelial Growth Factor Receptor-1 - genetics; Vascular Endothelial Growth Factor Receptor-1 - immunology; Vascular Endothelial Growth Factor Receptor-1 - metabolism; Human; retinal diseases; Eye disease; Vertebrata; Mammalia; Retinopathy; Primates; Neovascularization; Gene therapy; immunology
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2011.169

We report on the long-term safety of AAV2.sFlt-1 (a recombinant adeno-associated virus serotype 2 carrying the soluble form of the Flt-1 receptor) injection into the subretinal space of non-human primates. Levels of sFlt-1 protein were significantly higher (P<0.05) in the vitreous of four out of five AAV2.sFlt-1-injected eyes. There was no evidence of damage to the eyes of animals that received subretinal injections of AAV2.sFlt-1; ocular examination showed no anterior chamber flare, normal fundus and electroretinography responses equivalent to those observed before treatment. Notably, immunological analysis demonstrated that gene therapy involving subretinal injection of AAV2.sFlt-1 does not elicit cell-mediated immunity. Biodistribution analysis showed that AAV2.sFlt-1 could be detected only in the eye and not in the other organs tested. These data indicate that gene therapy with subretinal AAV2.sFlt-1 is safe and well tolerated, and therefore promising for the long-term treatment of neovascular diseases of the eye.