Research Article

AAV9-coGLB1 Improves Lysosomal Storage and Rescues Central Nervous System Inflammation in a Mutant Mouse Model of GM1 Gangliosidosis

Author(s): Sichi Liu, Wenhao Ma, Yuyu Feng, Yan Zhang, Xuefang Jia, Chengfang Tang, Fang Tang, Xiaobing Wu* and Yonglan Huang*

Volume 22, Issue 4, 2022

Published on: 01 April, 2022

Page: [352 - 365] Pages: 14

DOI: 10.2174/1566523222666220304092732

Price: $65


Background: GM1 gangliosidosis (GM1) is an autosomal recessive disorder characterized by the deficiency of beta-galactosidase (β-gal), a ubiquitous lysosomal enzyme that catalyzes the hydrolysis of GM1 ganglioside.

Objective: The study aims to explore the application of the AAV9-coGLB1 for effective treatment in a GM1 gangliosidosis mutant mouse model.

Methods: We designed a novel adeno-associated virus 9 (AAV9) vector expressing β-gal (AAV9- coGLB1) to treat GM1 gangliosidosis. The vector, injected via the caudal vein at 4 weeks of age, drove the widespread and sustained expression of β-gal for up to 32 weeks in the Glb1G455R/G455R mutant mice (GM1 mice).

Results: The increased levels of β-gal reduced the pathological damage occurring in GM1 mice. Histological analyses showed that myelin deficits and neuron-specific pathology were reduced in the cerebral cortex region of AAV9-coGLB1-treated mice. Immunohistochemical staining showed that the accumulation of GM1 ganglioside was also reduced after gene therapy. The reduction of the storage in these regions was accompanied by a decrease in activated microglia. In addition, AAV9 treatment reversed the blockade of autophagic flux in GM1 mice.

Conclusion: These results show that AAV9-coGLB1 reduces the pathological signs of GM1 gangliosidosis in a mouse model.

Keywords: GM1 gangliosidosis, mouse model, gene therapy, AAV9, central nervous system inflammation, autophagic flux.

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