Gene replacement therapies for inherited disorders of neurotransmission: Current progress in succinic semialdehyde dehydrogenase deficiency

J Inherit Metab Dis. 2024 May;47(3):476-493. doi: 10.1002/jimd.12735. Epub 2024 Apr 6.

Abstract

Neurodevelopment is a highly organized and complex process involving lasting and often irreversible changes in the central nervous system. Inherited disorders of neurotransmission (IDNT) are a group of genetic disorders where neurotransmission is primarily affected, resulting in abnormal brain development from early life, manifest as neurodevelopmental disorders and other chronic conditions. In principle, IDNT (particularly those of monogenic causes) are amenable to gene replacement therapy via precise genetic correction. However, practical challenges for gene replacement therapy remain major hurdles for its translation from bench to bedside. We discuss key considerations for the development of gene replacement therapies for IDNT. As an example, we describe our ongoing work on gene replacement therapy for succinic semialdehyde dehydrogenase deficiency, a GABA catabolic disorder.

Keywords: AAV; ALDH5A1; Dravet syndrome; GABA; KCC2; SLC6A1; autosomal dominant; autosomal recessive; delivery route; disease modeling; epilepsy; gene expression; genetic inheritance; haploinsufficiency; neurodevelopment; promoters; protein interaction; viral vector.

Publication types

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

MeSH terms

  • Amino Acid Metabolism, Inborn Errors* / genetics
  • Amino Acid Metabolism, Inborn Errors* / therapy
  • Animals
  • Genetic Therapy* / methods
  • Humans
  • Succinate-Semialdehyde Dehydrogenase* / deficiency
  • Succinate-Semialdehyde Dehydrogenase* / genetics
  • Synaptic Transmission* / genetics