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

Background: GM1 gangliosidosis (GM1) is an autosomal recessive disorder characterized by the deficiency of beta-galactosidase (beta-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 beta-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 beta-gal for up to 32 weeks in the Glb1(G455R/G455R) mutant mice (GM1 mice). Results: The increased levels of beta-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.