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Guylène Le Meur, MD; Michel Weber, MD, PhD; Yann Péréon, MD; Alexandra Mendes-Madeira, BS; Delphine Nivard, BS; Jack-Yves Deschamps, DVM; Philippe Moullier, MD, PhD; Fabienne Rolling, PhD

Arch Ophthalmol. 2005;123:500-506.

Objective  To evaluate, in dogs and primates, the short-term effects of subretinal injection and the safety of long-term recombinant adeno-associated virus (rAAV)–mediated transgene expression with respect to retinal morphology and function.

Methods  Subretinal delivery of rAAV (serotype 2, 4, or 5) was performed unilaterally in 14 beagles and 9 macaques. Postsurgical condition was evaluated during a 2-month follow-up study. Three dogs and 1 primate were examined for the long-term study. Green fluorescent protein expression was monitored by fluorescent retinal imaging. Retinal anatomy and function were assessed by angiography and electroretinography, respectively.

Results  Transgene expression was observed in 20 of 23 subretinally injected animals (both with and without vitrectomy). We did not detect an inflammatory response in any of the 23 treated subjects. In the long-term study, transgene expression was detected at the latest points evaluated: 36 months for the rAAV-2–injected dog, 24 months for the rAAV-4 and rAAV-5 dogs, and more than 18 months for the rAAV-4–injected primate. Angiography examinations were performed and showed no retinal abnormalities. Functional evaluation showed normal electroretinographic amplitude responses that were similar to those of the noninjected contralateral eyes.

Conclusions  Subretinal injection of the rAAV vector in dogs and primates is a safe procedure with no perioperative complications and a high rate of successful retinal gene transfer. The retinal anatomy and function remained unchanged, despite persistent transgene expression up to 36 months postinjection with rAAV-2, -4, or -5. Additionally, we observed no other adverse effects, such as tumor formation due to possible insertional mutagenesis. These short- and long-term studies on rAAV transgene expression using large animals are encouraging for the prospects of ocular gene therapy applications in humans.

Clinical Relevance  These short- and long-term studies on rAAV transgene expression using large animals are encouraging for the prospects of ocular gene therapy applications in humans.

Author Affiliations: Institut National de la Santé et de la Récherche Médicale UMR U649 (Drs Le Meur, Moullier, and Rolling and Mss Mendes-Madeira and Nivard), Service d’Ophtalmologie (Dr Weber), and Laboratoire d’Exploration Fonctionnelle (Dr Péréon), Centre Hospitalier Universitaire–Hotel Dieu, Ecole Nationale Veterinaire de Nantes (Dr Deschamps), Nantes, France.

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