Year: 2023
Type: article
Abstract: GM3 synthase deficiency (GM3SD) is an infantile-onset epileptic encephalopathy syndrome caused by biallelic loss-of-function mutations in ST3GAL5. Loss of ST3GAL5 activity in humans results in systemic ganglioside deficiency and severe neurological impairment. No disease-modifying treatment is currently available. Certain recombinant adeno-associated viruses (rAAVs) can cross the blood-brain barrier to induce widespread, long-term gene expression in the CNS and represent a promising therapeutic strategy. Here, we show that a first-generation rAAV-ST3GAL5 replacement vector using a ubiquitous promoter restored tissue ST3GAL5 expression and normalized cerebral gangliosides in patient-derived induced pluripotent stem cell neurons and brain tissue from St3gal5-KO mice but caused fatal hepatotoxicity when administered systemically. In contrast, a second-generation vector optimized for CNS-restricted ST3GAL5 expression, administered by either the intracerebroventricular or i.v. route at P1, allowed for safe and effective rescue of lethality and behavior impairment in symptomatic GM3SD mice up to a year. These results support further clinical development of ST3GAL5 gene therapy.
Source: JCI Insight
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,100
Funders: Regeneron Pharmaceuticals, National Institutes of Health, University of Massachusetts Medical School, National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: Fortilin, CTNNA3, and the Heart, New Approaches to Gene Therapy for Alpha-1 Antitrypsin Deficiency, Fcgamma receptor-mediated suppression of immunodeficiency virus replication, Next Generation of Recombinant AAV Serotype For Gene Therapy, Develop combinatorial non-viral and viral CRISPR delivery for lung diseases, An AAV-mediated functional cure and its impact on the reservoir, A novel bone-targeting AAV-mediated gene therapy to promote bone formation in osteoporosis, Develop combinatorial non-viral and viral CRISPR delivery for lung diseases, Models and Gene Therapies for AAT Deficiency, Oligodendrocyte-focused rAAV gene therapy strategies for Canavan disease and Leukodystrophies
OpenAlex ID: W4362522609