1. ¹INSERM UMR 649, CHU de Nantes, Université de Nantes, Faculté de Médecine, Nantes, France
2. ²INRA UMR 703, Ecole Nationale Vétérinaire, Nantes, France
3. ³INSERM UMR 643, CHU de Nantes, Institut de Transplantation et de Recherche en Transplantation, Faculté de Médecine, Université de Nantes, Nantes, France
4. ⁴Service de Chirurgie, Ecole Nationale Vétérinaire, Nantes, France
5. ⁵Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA

Correspondence: Caroline Le Guiner, INSERM UMR 649, IRT 1, Université de Nantes, 8, quai Moncousu, BP 70721, 44007 Nantes Cedex 1, France. E-mail: caroline.le-guiner@univ-nantes.fr

The first two authors contributed equally to this work.

Received 21 November 2008; Accepted 27 September 2009; Published online 3 November 2009.

Abstract

In the absence of an immune response from the host, intramuscular (IM) injection of recombinant adeno-associated virus (rAAV) results in the permanent expression of the transgene from mouse to primate models. However, recent gene transfer studies into animal models and humans indicate that the risk of transgene and/or capsid-specific immune responses occurs and depends on multiple factors. Among these factors, the route of delivery is important, although poorly addressed in large animal models. Here, we compare the IM and the drug-free regional intravenous (RI) deliveries of rAAV in nonhuman primate (NHP) skeletal muscle monitoring the host immune response toward the transgene. We show that IM is consistently associated with immunotoxicity and the destruction of the genetically modified myofibers, whereas RI allows the stable expression of the transgene. This has important implications for the design of clinical trials for gene transfer in skeletal muscle.