Open AccessA Single Injection of an Optimized Adeno-Associated Viral Vector into Cerebrospinal Fluid Corrects Neurological Disease in a Murine Model of GM1 Gangliosidosis
Author(s) -
Christian Hinderer,
Brenden Nosratbakhsh,
Nathan Katz,
James M. Wilson
Publication year - 2020
Publication title -
human gene therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.633
H-Index - 149
eISSN - 1557-7422
pISSN - 1043-0342
DOI - 10.1089/hum.2018.206
Subject(s) - gangliosidosis , cerebrospinal fluid , vector (molecular biology) , viral vector , genetic enhancement , lysosomal storage disease , medicine , adeno associated virus , disease , pathology , biology , virology , gene , biochemistry , recombinant dna
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.