Human Molecular Genetics Advance Access [Accepted Manuscript] published online on October 16, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp475
EFFICIENT INTRACEREBRAL DELIVERY OF AAV5 VECTOR ENCODING HUMAN ARSA IN NON-HUMAN PRIMATE
,1,2,2,2,*1 UMR INRA 703, Ecole Vétérinaire de Nantes, Nantes, France 2 UMR INSERM 745 and University Paris-Descartes, Paris, France 3 University of Nantes, CHU Nord, Service de Neurochirurgie, Nantes, France 4 INSERM U649, University of Nantes, Nantes, France and Department of Molecular Genetics & Microbiology, University of Florida, Gainesville, USA
* Corresponding author: Caroline Sevin, INSERM UMR745, Faculté des Sciences Pharmaceutiques et Biologiques-Paris5, 4 Avenue de l'Observatoire, 75279 PARIS cedex 06., Phone: +33 1 70 64 94 02, Fax: +33 1 40 48 84 39, E-mail: caroline.sevin{at}inserm.fr
Received August 12, 2009; Revised October 12, 2009; Accepted October 12, 2009
Metachromatic leukodystrophy is a lethal neurodegenerative disease caused by a deficiency in the lysosomal arylsulfatase A (ARSA) enzyme leading to the accumulation of sulfatides in glial and neuronal cells. We previously demonstrated in ARSA deficient mice that intracerebral injection of a serotype 5 adeno-associated viral vector (AAV) encoding human ARSA corrects the biochemical, neuropathological and behavioral abnormalities. However, before considering a potential clinical application, scaling-up issues should be addressed in large animals. Therefore, we performed intracerebral injection of the same AAV vector (total dose of 3.8x1011 or 1.9x1012 vector genome, 3 sites of injection in the right hemisphere, 2 deposits per site of injection) into three selected areas of the centrum semiovale white matter, or in the deep grey matter nuclei (caudate nucleus, putamen, thalamus) of 6 non-human primates to evaluate vector distribution, as well as expression and activity of human ARSA. The procedure was perfectly tolerated, without any adverse effect or change in neurobehavioral examination. AAV vector was detected in a brain volume of 12-15 cm3 that corresponded to 37-46% of the injected hemisphere. ARSA enzyme was expressed in multiple interconnected brain areas over a distance of 22-33 mm. ARSA activity was increased by 12-38% in a brain volume that corresponded to 50-65% of injected hemisphere. These data provide substantial evidence for potential benefits of brain gene therapy in patients with metachromatic leukodystrophy.
These authors contributed equally to this work