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

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 GABA 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.

Preclinical tissue distribution and metabolic correlations of vigabatrin, an antiepileptic drug associated with potential use‐limiting visual field defects

“…The role(s) of GABA, β‐alanine and 4‐GBA in the ocular toxicity of VGB remain unknown. Conversely, we and others have demonstrated that supraphysiological GABA impacts the mTOR pathway of autophagy, leading to mitochondrial accumulation and enhanced oxidative stress . β‐Alanine, the structural homologue of GABA, has GABAergic and glycinergic roles that are well‐described, but its role in VGB‐mediated toxicity has not been investigated.…”

“…Conversely, we and others have demonstrated that supraphysiological GABA impacts the mTOR pathway of autophagy, leading to mitochondrial accumulation and enhanced oxidative stress. 10,11,[50][51][52] β-Alanine, the structural homologue of GABA, has GABAergic and glycinergic roles that are well-described, 53 F I G U R E 1 2 Tissue pools of VGB enantiomers as a function of VGB dose. ND, Not Determined -Prefrontal cortex samples from animals treated with the 35 mg/kg/d dose were used for RNA isolation and thus were unavailable for enantiomer analysis.…”

Succinic Semialdehyde Dehydrogenase Deficiency: An Update

“…In addition, higher mRNA levels of GABA receptor genes were detected in the treated mice. Highly intriguingly, the authors demonstrated significantly decreased brain GHB levels in the treated mice, implicating that the peripherally administrated recombinant SSADH enzyme was capable of clearing the brain GHB excess [70]. This is an important indication for a possible ERT-based treatment in SSADH-D patients with recombinant SSADH, especially in terms of the route of administration.…”

“…These treatment concepts and previous clinical trials are summarized in the following paragraphs and in Table 2. Since the treatments and clinical trials have recently been excellently addressed by Vogel and colleagues, we here only shortly summarize the trials and the rationale of these treatments [70]. [84,85] Neuroprotective effects Improves survival of aldh5a -/mice [84,85] Neuroprotective effects…”

“…To date, there is only one report on ERT for SSADH-D in the knockout mouse model [70]. Vogel and coauthors produced a glutathione S-transferase (GST) -tagged SSADH fusion protein in a bacterial expression system.…”