Liver-directed adenoviral gene transfer in murine succinate semialdehyde dehydrogenase deficiency

Maneesh Gupta, Erwin E.W. Jansen, Henry Senephansiri, Cornelis Jakobs, O. Carter Snead, Markus Grompe, K. Michael Gibson

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Murine succinate semialdehyde dehydrogenase (SSADH) deficiency (OMIM 271980; EC, a model of the corresponding human disorder, displays 100% mortality at weeks 3-4 of life, associated with lethal tonic-clonic seizures. The biochemical hallmark, γ-hydroxybutyrate (GHB), accumulates in both human and murine disorders. In the current study we evaluated rescue of the murine model with liver-directed gene therapy using the E1-deleted adenoviral vector AD:pAD-RSV-humanSSADH. Our working hypotheses were: (1) liver expresses considerable SSADH activity and therefore represents a major source of GHB output, (2) correction of liver enzyme deficiency will reduce GHB load both peripherally and in the central nervous system, and (3) SSADH expression will improve survival. SSADH-/- and SSADH+/+ mice were treated under two protocols: (A) intraperitoneal injection of 108-1011 viral particles by day 10 of life or (B) retro-orbital injection of 1011 viral particles at day 13 of life. Intravenous administration was prohibited by the small size and fragility of the mice. Maximal survival (39%; P < 0.001) was achieved with intraperitoneal administration (108 particles) at day 10; intraperitoneal (1010 and 1011 particles) and retro-orbital administration (1011 particles) yielded lower survival of 11-25% (P < 0.02). Under both protocols, the maximal hepatic SSADH enzyme activity was ∼20% of SSADH+/+ liver activity (retro-orbital > ip). At various time points postinjection, ip-treated animals (108 viral particles) demonstrated upward of 80% reduction in liver GHB concentrations, with little impact on brain or serum GHB levels except at 48-72 h posttreatment (∼50% reduction for both tissues). Accordingly, we harvested retro-orbitally treated animals at 72 h and observed significant reductions of 60-70% for GHB in liver, kidney, serum, and brain extracts. Histochemical analysis of liver from retro-orbitally treated mutants demonstrated substantial SSADH staining, but with variability both within tissues and between animals. Our studies provide proof-of-principle that liver-mediated gene therapy has efficacy in treating SSADH deficiency and that hepatic tissue contributes significantly to the pool of GHB within the CNS.

Original languageEnglish (US)
Pages (from-to)527-539
Number of pages13
JournalMolecular Therapy
Issue number4
StatePublished - Apr 2004


  • Adenoviridae
  • Brain disease, inborn, metabolic
  • Disease models, animal
  • Gene therapy
  • Genetic vectors
  • Liver
  • Seizures
  • Succinate semialdehyde dehydrogenase
  • γ -hydroxybutyric acid
  • γ-aminobutyric acid

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery


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