Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme-replacement therapeutic strategies

Kara R. Vogel, Garrett R. Ainslie, Dana C. Walters, Alice McConnell, Sameer C. Dhamne, Alexander Rotenberg, Jean-Baptiste Roullet, K. Michael Gibson

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

We present an update to the status of research on succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD), a rare disorder of GABA metabolism. This is an unusual disorder featuring the accumulation of both GABA and its neuromodulatory analog, gamma-hydroxybutyric acid (GHB), and recent studies have advanced the potential clinical application of NCS-382, a putative GHB receptor antagonist. Animal studies have provided proof-of-concept that enzyme replacement therapy could represent a long-term therapeutic option. The characterization of neuronal stem cells (NSCs) derived from aldehyde dehydrogenase 5a1−/− (aldh5a1−/−) mice, the murine model of SSADHD, has highlighted NSC utility as an in vitro system in which to study therapeutics and associated toxicological properties. Gene expression analyses have revealed that transcripts encoding GABAA receptors are down-regulated and may remain largely immature in aldh5a1−/− brain, characterized by excitatory as opposed to inhibitory outputs, the latter being the expected action in the mature central nervous system. This indicates that agents altering chloride channel activity may be therapeutically relevant in SSADHD. The most recent therapeutic prospects include mTOR (mechanistic target of rapamycin) inhibitors, drugs that have received attention with the elucidation of the effects of elevated GABA on autophagy. The outlook for novel therapeutic trials in SSADHD continues to improve.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalJournal of Inherited Metabolic Disease
DOIs
StateAccepted/In press - Feb 19 2018
Externally publishedYes

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gamma-Aminobutyric Acid
Pharmacology
Enzymes
Aldehyde Dehydrogenase
Therapeutics
Stem Cells
Enzyme Replacement Therapy
Chloride Channels
Autophagy
GABA-A Receptors
Sirolimus
succinic semialdehyde dehydrogenase deficiency
Toxicology
Central Nervous System
Gene Expression
Brain
Research
Pharmaceutical Preparations

Keywords

  • Enzyme replacement therapy
  • GABA
  • Gamma-hydroxybutyric aciduria
  • mTOR
  • Succinic semialdehyde dehydrogenase deficiency
  • Torin 2

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism : an update on pharmacological and enzyme-replacement therapeutic strategies. / Vogel, Kara R.; Ainslie, Garrett R.; Walters, Dana C.; McConnell, Alice; Dhamne, Sameer C.; Rotenberg, Alexander; Roullet, Jean-Baptiste; Gibson, K. Michael.

In: Journal of Inherited Metabolic Disease, 19.02.2018, p. 1-10.

Research output: Contribution to journalArticle

Vogel, Kara R. ; Ainslie, Garrett R. ; Walters, Dana C. ; McConnell, Alice ; Dhamne, Sameer C. ; Rotenberg, Alexander ; Roullet, Jean-Baptiste ; Gibson, K. Michael. / Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism : an update on pharmacological and enzyme-replacement therapeutic strategies. In: Journal of Inherited Metabolic Disease. 2018 ; pp. 1-10.
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