Human alpha-iduronidase gene transfer mediated by adeno-associated virus types 1, 2, and 5 in the brain of nonhuman primates: vector diffusion and biodistribution.
We have previously demonstrated that delivery of a recombinant adeno-associated virus (rAAV) encoding human alpha-iduronidase (hIDUA) in the putamen and centrum semiovale was feasible and beneficial in a dog model of Hurler's syndrome. In the present study, we investigated the safety and vector diffusion profile of three rAAV serotypes (rAAV2/1, rAAV2/2, and rAAV2/5), encoding hIDUA in the central and peripheral nervous systems of nonhuman primates. Six macaques received the same vector dose injected into the right putamen and the homolateral internal capsule. Neurological examinations were done regularly and showed no detectable clinical consequence of the intracerebral injections. Because transgene IDUA was indistinguishable from endogenous enzymatic activity, we looked for vector diffusion by performing quantitative polymerase chain reaction on serial sections from the brain and spinal cord. We found that global diffusion throughout the brain was not significantly different between the three serotypes. However, rAAV2/1 and rAAV2/5 resulted in higher vector copy numbers per cell than did rAAV2/2, respectively, in the brain and the distal neuronal structures (spinal cord and peripheral nerves).
Ciron
Carine
C
INSERM U649, 44000 Nantes, France.
Cressant
Arnaud
A
Roux
Françoise
F
Raoul
Sylvie
S
Cherel
Yan
Y
Hantraye
Philippe
P
Déglon
Nicole
N
Schwartz
Bertrand
B
Barkats
Martine
M
Heard
Jean-Michel
JM
Tardieu
Marc
M
Moullier
Philippe
P
Colle
Marie-Anne
MA
D000818:Animals; D001921:Brain / Q000378:metabolism*; D003391:Cranial Nerves / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D004058:Diffusion; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016679:Genome, Viral; D006801:Humans; D007068:Iduronidase / Q000235:genetics*; D007276:Injections, Intraventricular; D020772:Internal Capsule / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008251:Macaca / Q000235:genetics*; D009928:Organ Specificity; D010525:Peripheral Nerves / Q000378:metabolism; D011699:Putamen / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D014018:Tissue Distribution; D019076:Transgenes; D014771:Virion / Q000235:genetics
D007068:Iduronidase