Department of Guangzhou Newborn Screening Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou Guangdong 510623, China.
Beijing Ruicy Gene Therapy Institute For Rare Diseases, Beijing, China.
Curr Gene Ther. 2022;22(4):352-365. doi: 10.2174/1566523222666220304092732.
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.
The study aims to explore the application of the AAV9-coGLB1 for effective treatment in a GM1 gangliosidosis mutant mouse model.
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 Glb1 mutant mice (GM1 mice).
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.
These results show that AAV9-coGLB1 reduces the pathological signs of GM1 gangliosidosis in a mouse model.
GM1 神经节苷脂贮积症（GM1）是一种常染色体隐性遗传病，其特征是β-半乳糖苷酶（β-gal）缺乏，β-gal 是一种普遍存在的溶酶体酶，能够催化 GM1 神经节苷脂的水解。
本研究旨在探讨使用 AAV9-coGLB1 治疗 GM1 神经节苷脂贮积症突变小鼠模型的应用。
我们设计了一种新型腺相关病毒 9（AAV9）载体，表达β-半乳糖苷酶（AAV9-coGLB1），用于治疗 GM1 神经节苷脂贮积症。该载体通过尾静脉在 4 周龄时注射，可在 Glb1 突变小鼠（GM1 小鼠）中驱动β-gal 的广泛和持续表达，最长可达 32 周。
β-gal 水平的增加减轻了 GM1 小鼠的病理损伤。组织学分析显示，AAV9-coGLB1 治疗组小鼠大脑皮质区域的髓鞘缺失和神经元特异性病变减少。免疫组织化学染色显示，基因治疗后 GM1 神经节苷脂的蓄积也减少。这些区域的储存减少伴随着激活的小胶质细胞减少。此外，AAV9 治疗逆转了 GM1 小鼠自噬流的阻断。
这些结果表明，AAV9-coGLB1 可减轻 GM1 神经节苷脂贮积症小鼠模型的病理表现。
