Transduction of Photoreceptors With Equine Infectious Anemia Virus Lentiviral Vectors: Safety and Biodistribution of StarGen for Stargardt Disease

• Type of Material: Article
• Authors: Katie Binley, Oxford BioMedica (UK) Ltd; Peter Widdowson, Oxford BioMedica (UK) Ltd; Julie Loader, Oxford BioMedica (UK) Ltd; Michelle Kelleher, Oxford BioMedica (UK) Ltd; Sharifah Iqball, Oxford BioMedica (UK) Ltd; Georgina Ferrige, Oxford BioMedica (UK) Ltd; Jackie de Belin, Oxford BioMedica (UK) Ltd; Marie Carlucci, Oxford BioMedica (UK) Ltd; Diana Angell-Manning, Oxford BioMedica (UK) Ltd; Felicity Hurst, Oxford BioMedica (UK) Ltd; Scott Ellis, Oxford BioMedica (UK) Ltd; James Miskin, Oxford BioMedica (UK) Ltd; Alcides Fernandes, Emory University; Paul Wong, Emory University; Rando Allikmets, Columbia University; Christopher Bergstrom, Emory University; Thomas M. Aaberg, Jr., Emory University; Jiong Yan, Emory University; Jiong Kong, Columbia University; Peter Gouras, Columbia University; Annick Prefontaine, Preclinical Services Montreal; Mark Vezina, Preclinical Services Montreal; Martin Bussieres, Preclinical Services Montreal; Stuart Naylor, Oxford BioMedica (UK) Ltd; Kyriacos A. Mitrophanous, Oxford BioMedica (UK) Ltd
• Language: English
• Date: 2013-06-01
• Publisher: Association for Research in Vision and Ophthalmology (ARVO)
• Publication Version: Final Published Version
• Copyright Statement: © 2013 The Association for Research in Vision and Ophthalmology, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1167/iovs.13-11871
• Title of Journal or Parent Work: Investigative Ophthalmology & Visual Science
• ISSN: 0146-0404
• Volume: 54
• Issue: 6
• Start Page: 4061
• End Page: 4071
• Grant/Funding Information: Supported in part by funds from the Foundation Fighting Blindness, Columbia, Maryland (RA, JK, PG), National Eye Institute/National Institutes of Health Grant R24 EY019861 (RA, JK, PG), and an unrestricted grant to the Department of Ophthalmology, Columbia University, New York, New York, from Research to Prevent Blindness, Inc.
• Keywords: MACULAR DEGENERATION; ABCR; MUTATIONS; Science & Technology; DYSTROPHY; LEBERS CONGENITAL AMAUROSIS; Life Sciences & Biomedicine; Ophthalmology; EXPRESSION; gene therapy; photoreceptors; N-RETINYLIDENE-PHOSPHATIDYLETHANOLAMINE; RETINITIS-PIGMENTOSA; SUBRETINAL INJECTION; GENE-THERAPY; lentivirus
• Research Categories: Biology, Virology; Health Sciences, Public Health

Abstract

PURPOSE. StarGen is an equine infectious anemia virus (EIAV)-based lentiviral vector that expresses the photoreceptor-specific adenosine triphosphate (ATP)-binding cassette transporter (ABCA4) protein that is mutated in Stargardt disease (STGD1), a juvenile macular dystrophy. EIAV vectors are able to efficiently transduce rod and cone photoreceptors in addition to retinal pigment epithelium in the adult macaque and rabbit retina following subretinal delivery. The safety and biodistribution of StarGen following subretinal delivery in macaques and rabbits was assessed. METHODS. Regular ophthalmic examinations, IOP measurements, ERG responses, and histopathology were carried out in both species to compare control and vector-treated eyes. Tissue and fluid samples were obtained to evaluate the persistence, biodistribution, and shedding of the vector following subretinal delivery. RESULTS. Ophthalmic examinations revealed a slightly higher level of inflammation in StarGen compared with control treated eyes in both species. However, inflammation was transient and no overt toxicity was observed in StarGen treated eyes and there were no abnormal clinical findings. There was no StarGen-associated rise in IOP or abnormal ERG response in either rabbits or macaques. Histopathologic examination of the eyes did not reveal any detrimental changes resulting from subretinal administration of StarGen. Although antibodies to StarGen vector components were detected in rabbit but not macaque serum, this immunologic response did not result in any long-term toxicity. Biodistribution analysis demonstrated that the StarGen vector was restricted to the ocular compartment. CONCLUSIONS. In summary, these studies demonstrate StarGen to be well tolerated and localized following subretinal administration.