Adeno-associated virus type 5 reduces learning deficits and restores glutamate receptor subunit levels in MPS VII mice CNS.

Abstract

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.

• Authors: Gumei Liu, Yong Hong Chen, Xiaohua He, Inês Martins, Jason A Heth, John A Chiorini, Beverly L Davidson
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 15 Issue 2 Pg. 242-7 (Feb 2007) ISSN: 1525-0016 [Print] United States
• PMID: 17235300 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Glutamate
• Receptors, N-Methyl-D-Aspartate
• alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
• Glucuronidase

Topics

• Adenoviridae (genetics)
• Animals
• Blotting, Western
• Brain (metabolism)
• Central Nervous System (metabolism)
• Genetic Therapy (methods)
• Genetic Vectors (genetics)
• Glucuronidase (genetics, metabolism)
• Hippocampus (metabolism)
• Learning Disabilities (physiopathology, therapy)
• Memory (physiology)
• Mice
• Mucopolysaccharidosis VII (physiopathology)
• Receptors, Glutamate (metabolism)
• Receptors, N-Methyl-D-Aspartate (genetics, metabolism)
• alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (metabolism)