Rescue of GM3 synthase deficiency by spatially controlled, rAAV-mediated ST3GAL5 delivery

JCI Insight. 2023 May 8;8(9):e168688. doi: 10.1172/jci.insight.168688.


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.

Keywords: Gene therapy; Neurological disorders; Neuroscience; Therapeutics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Epilepsy* / genetics
  • Gangliosides / genetics
  • Humans
  • Mice
  • Mutation
  • Sialyltransferases / genetics
  • Sialyltransferases / metabolism


  • Gangliosides
  • Sialyltransferases

Supplementary concepts

  • Amish Infantile Epilepsy Syndrome