Retinal transduction profiles by high-capacity viral vectors

• Type of Material: Article
• Authors: Agostina Puppo, Telethon Institute of Genetics and Medicine; Giulia Cesi, Telethon Institute of Genetics and Medicine; Elena Marrocco, Telethon Institute of Genetics and Medicine; Pasquale Piccolo, Telethon Institute of Genetics and Medicine; Sarah Jacca, University of Parma; Dmitry Shayakhmetov, Emory University; Robin J. Parks, Ottawa Hospital Research Institute; Beverly L. Davidson, University of Iowa; Stefano Colloca, Okairos; Nicola Brunetti-Pierri, Telethon Institute of Genetics and Medicine; Philip Ng, Baylor College of Medicine; Gaetano Donofrio, University of Parma; Alberto Auricchio, Telethon Institute of Genetics and Medicine
• Language: English
• Date: 2014-10-01
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Macmillan Publishers Limited All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/gt.2014.57
• Title of Journal or Parent Work: Gene Therapy
• Volume: 21
• Issue: 10
• Start Page: 855
• End Page: 865
• Grant/Funding Information: This work was supported by the European Research Council/ERC Grant agreement n° 282085 “RetGeneTx”; the NIH (grant R24 EY019861-01A); the Italian Telethon Foundation (grant TGM11MT1).
• Keywords: CORNEAL ENDOTHELIUM; NONHUMAN-PRIMATES; Biochemistry & Molecular Biology; MOUSE MODEL; Medicine, Research & Experimental; DEPENDENT ADENOVIRAL VECTORS; Science & Technology; BOVINE HERPESVIRUS-4; Biotechnology & Applied Microbiology; Genetics & Heredity; LENTIVIRAL VECTOR; IN-VIVO; MEDIATED GENE-TRANSFER; Life Sciences & Biomedicine; SUBRETINAL INJECTION; TRANSGENE EXPRESSION; Research & Experimental Medicine
• Research Categories: Chemistry, Biochemistry

Abstract

Retinal gene therapy with adeno-associated viral (AAV) vectors is safe and effective in humans. However, the limited cargo capacity of AAV prevents their use for therapy of those inherited retinopathies (IRs) due to mutations in large (>5 kb) genes. Viral vectors derived from adenovirus (Ad), lentivirus (LV) and herpes virus (HV) can package large DNA sequences, but do not target efficiently retinal photoreceptors (PRs) where the majority of genes responsible for IRs are expressed. Here, we have evaluated the mouse retinal transduction profiles of vectors derived from 16 different Ad serotypes, 7 LV pseudotypes and from a bovine HV. Most of the vectors tested transduced efficiently the retinal pigment epithelium. We found that LV-GP64 tends to transduce more PRs than the canonical LV-VSVG, albeit this was restricted to a narrow region. We observed more extensive PR transduction with HdAd1, 2 and 5/F35++ than with LV, although none of them outperformed the canonical HdAd5 or matched the extension of PR transduction achieved with AAV2/8.