Feasibility and safety of systemic rAAV9-hNAGLU delivery for treating mucopolysaccharidosis IIIB: toxicology, biodistribution, and immunological assessments in primates.
No treatment is currently available for mucopolysaccharidosis (MPS) IIIB, a neuropathic lysosomal storage disease caused by autosomal recessive defect in α-N-acetylglucosaminidase (NAGLU). In anticipation of a clinical gene therapy treatment for MPS IIIB in humans, we tested the rAAV9-CMV-hNAGLU vector administration to cynomolgus monkeys (n=8) at 1E13 vg/kg or 2E13 vg/kg via intravenous injection. No adverse events or detectable toxicity occurred over a 6-month period. Gene delivery resulted in persistent global central nervous system and broad somatic transduction, with NAGLU activity detected at 2.9-12-fold above endogenous levels in somatic tissues and 1.3-3-fold above endogenous levels in the brain. Secreted rNAGLU was detected in serum. Low levels of preexisting anti-AAV9 antibodies (Abs) did not diminish vector transduction. Importantly, high-level preexisting anti-AAV9 Abs lead to reduced transduction in liver and other somatic tissues, but had no detectable impact on transgene expression in the brain. Enzyme-linked immunoabsorbent assay showed Ab responses to both AAV9 and rNAGLU in treated animals. Serum anti-hNAGLU Abs, but not anti-AAV9 Abs, correlated with the loss of circulating rNAGLU enzyme. However, serum Abs did not affect tissue rNAGLU activity levels. Weekly or monthly peripheral blood interferon-γ enzyme-linked immunospot assays detected a CD4(+) T-cell (Th-1) response to rNAGLU only at 4 weeks postinjection in one treated subject, without observable correlation to tissue transduction levels. The treatment did not result in detectable CTL responses to either AAV9 or rNAGLU. Our data demonstrate an effective and safe profile for systemic rAAV9-hNAGLU vector delivery in nonhuman primates, supporting its clinical potential in humans.
1 Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital , Columbus, OH 43205.
Darren A
DA
Murrey
Bartholomew J
BJ
Naughton
F Jason
FJ
Duncan
Aaron S
AS
Meadows
Tierra A
TA
Ware
Katie J
KJ
Campbell
William G
WG
Bremer
Christopher M
CM
Walker
Laurie
L
Goodchild
Brad
B
Bolon
Krista
K
La Perle
Kevin M
KM
Flanigan
Kim L
KL
McBride
Douglas M
DM
McCarty
Haiyan
H
Fu
D000118:Acetylglucosaminidase / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000097:blood / Q000276:immunology; D001921:Brain / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics* / Q000276:immunology; D058501:Enzyme-Linked Immunospot Assay; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008252:Macaca fascicularis; D009084:Mucopolysaccharidosis III / Q000628:therapy*; D011994:Recombinant Proteins / Q000097:blood / Q000134:cerebrospinal fluid; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D014018:Tissue Distribution
D000906:Antibodies; D011994:Recombinant Proteins; C033079:alpha-N-acetyl-D-glucosaminidase; D000118:Acetylglucosaminidase