Adeno-associated virus type 5 reduces learning deficits and restores glutamate receptor subunit levels in MPS VII mice CNS.
A major challenge in treating lysosomal storage diseases with enzyme therapy is correcting symptoms in the central nervous system (CNS). This study used a murine model of mucopolysaccharidosis type VII (MPS VII) to test whether pathological and functional CNS defects could be corrected by expressing beta-glucuronidase via bilateral intrastriatal injection of adeno-associated virus type 5 (AAV5betagluc) vectors. After injecting AAV5betagluc, different brain regions expressed active beta-glucuronidase, which corrected lysosomal storage defects. Compared to age-matched littermates, adult MPS VII mice were impaired in spatial learning and memory, as measured by the repeated acquisition and performance chamber (RAPC) assay. AAV5betagluc-treated MPS VII mice improved significantly in the RAPC assay, relative to saline-injected littermates. Moreover, our studies reveal that cognitive changes in MPS VII mice correlate with decreased N-methyl-d-aspartate and alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptor expression. Importantly, AAV5betagluc delivery restored glutamate receptor levels. Together, these data demonstrate that AAV5 vectors deliver a therapeutically effective beta-glucuronidase gene to the CNS and further suggest a possible mechanism underlying spatial learning defects in MPS VII mice.
Liu
Gumei
G
Program in Gene Therapy, Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
Chen
Yong Hong
YH
He
Xiaohua
X
Martins
Inês
I
Heth
Jason A
JA
Chiorini
John A
JA
Davidson
Beverly L
BL
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007859:Learning Disabilities / Q000503:physiopathology / Q000628:therapy*; D008568:Memory / Q000502:physiology; D051379:Mice; D016538:Mucopolysaccharidosis VII / Q000503:physiopathology*; D017470:Receptors, Glutamate / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D005966:Glucuronidase