Related Experiment Video
Updated: Oct 9, 2026
Direct Intrathecal Injection of Recombinant Adeno-associated Viruses in Adult Mice
Published on: February 15, 2019
Intracranial injection of recombinant adeno-associated virus improves cognitive function in a murine model of
W A Frisella1, L H O'Connor, C A Vogler
1Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Abstract:
Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by the lack of beta-glucuronidase (GUSB) activity. GUSB deficiency leads to the progressive accumulation of undegraded glycosaminoglycans (GAGs) in cells of most tissues, including the brain, and is associated with mental retardation. Reduction of lysosomal storage in the central nervous system and prevention of cognitive dysfunction may require intracranial delivery of a therapeutic agent during the newborn period that provides a continuous source of GUSB. Therefore, we injected recombinant adeno-associated virus encoding human GUSB into both the anterior cortex and the hippocampus of newborn MPS VII mice. Total GUSB activity in the brain approached normal levels by 18 weeks. Although GUSB activity was concentrated near the injection sites, lysosomal distension was reduced in most areas of the brain. In addition to histopathologic evidence of GAG reduction, the previously undescribed accumulation of GM2 and GM3 gangliosides in the brain was also prevented. Furthermore, GUSB expression and reduced lysosomal distension correlated with improvements in cognitive function as measured in the Morris Water Maze test. These findings indicate that localized overexpression of GUSB has positive effects on the pathology and cognitive function and does not have overt toxicity.
Insights
Gene therapy for Mucopolysaccharidosis type VII (MPS VII) using adeno-associated virus delivered beta-glucuronidase (GUSB) to newborn mice. This treatment reduced GAG storage and improved cognitive function, showing therapeutic potential.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Mucopolysaccharidosis type VII (MPS VII) is a rare genetic lysosomal storage disease.
- Deficiency in beta-glucuronidase (GUSB) activity leads to progressive accumulation of glycosaminoglycans (GAGs).
- This accumulation, particularly in the central nervous system, causes mental retardation and cognitive dysfunction.
Purpose of the Study:
- To investigate the efficacy of intracranial delivery of adeno-associated virus (AAV)-GUSB in newborn MPS VII mice.
- To assess the reduction of lysosomal storage and improvement in cognitive function.
- To evaluate the safety and toxicity of the AAV-GUSB gene therapy approach.
Main Methods:
- Newborn MPS VII mice were injected with AAV encoding human GUSB into the anterior cortex and hippocampus.
- GUSB activity, GAG levels, and lysosomal morphology were analyzed in brain tissues.
- Cognitive function was assessed using the Morris Water Maze test.
Main Results:
- Intracranial AAV-GUSB injection normalized brain GUSB activity by 18 weeks.
- Lysosomal distension and GAG accumulation were significantly reduced throughout the brain.
- GM2 and GM3 ganglioside accumulation was prevented, and cognitive function improved.
Conclusions:
- Localized AAV-mediated GUSB overexpression effectively reduces neuropathology in MPS VII mice.
- This gene therapy approach demonstrates potential for preventing cognitive decline in MPS VII.
- The treatment showed no overt toxicity, supporting its therapeutic promise.
