Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
Hum Gene Ther. 2020 Nov;31(21-22):1169-1177. doi: 10.1089/hum.2018.206. Epub 2020 Nov 2.
GM1 gangliosidosis is a rare neurodegenerative lysosomal storage disease caused by loss-of-function mutations in the gene encoding beta-galactosidase (β-gal). There are no approved treatments for GM1 gangliosidosis. Previous studies in animal models have demonstrated that adeno-associated viral (AAV) vector-mediated gene transfer to the brain can restore β-gal expression and prevent the onset of neurological signs. We developed an optimized AAV vector expressing human β-gal and evaluated the efficacy of a single intracerebroventricular injection of this vector into the cerebrospinal fluid (CSF) of a murine disease model. The AAV vector administration into the CSF increased β-gal activity in the brain, reduced neuronal lysosomal storage lesions, prevented the onset of neurological signs and gait abnormalities, and increased survival. These findings demonstrate the potential therapeutic activity of this vector and support its subsequent development for the treatment of GM1 gangliosidosis.
GM1 神经节苷脂贮积症是一种罕见的神经退行性溶酶体贮积病，由编码β-半乳糖苷酶（β-gal）的基因突变引起。目前尚无针对 GM1 神经节苷脂贮积症的批准治疗方法。以前在动物模型中的研究表明，腺相关病毒（AAV）载体介导的基因转移到大脑可以恢复β-gal 的表达并预防神经症状的发生。我们开发了一种表达人β-gal 的优化 AAV 载体，并评估了单次脑室内注射该载体到脑脊液（CSF）中的疗效在小鼠疾病模型中。CSF 中的 AAV 载体给药增加了大脑中的β-gal 活性，减少了神经元溶酶体贮积病变，预防了神经症状和步态异常的发生，并提高了生存率。这些发现表明该载体具有潜在的治疗活性，并支持其随后的开发用于治疗 GM1 神经节苷脂贮积症。
