Title:AAV9-coGLB1 Improves Lysosomal Storage and Rescues Central Nervous
System Inflammation in a Mutant Mouse Model of GM1 Gangliosidosis
Volume: 22
Issue: 4
Author(s): Sichi Liu, Wenhao Ma, Yuyu Feng, Yan Zhang, Xuefang Jia, Chengfang Tang, Fang Tang, Xiaobing Wu*Yonglan Huang*
Affiliation:
- Beijing Ruicy Gene Therapy Institute For Rare Diseases,
Beijing, China
- Department of Guangzhou Newborn Screening Center, Guangzhou Women and Children’s Medical Center, Guangzhou
Medical University, Guangzhou Guangdong 510623, China
Keywords:
GM1 gangliosidosis, mouse model, gene therapy, AAV9, central nervous system inflammation, autophagic flux.
Abstract:
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.
