Vol. 302, Issue 1, 180-187, July 2002

Therapeutic Intervention in Mice Deficient for Succinate Semialdehyde Dehydrogenase (-Hydroxybutyric Aciduria)

Maneesh Gupta, Rachel Greven, Erwin E. W. Jansen, Cornelis Jakobs, Boris M. Hogema , Wolfgang Froestl, O. Carter Snead, Hilke Bartels, Markus Grompe and K. Michael Gibson

Department of Molecular and Medical Genetics and Pediatrics, Oregon Health & Science University, Portland, Oregon (M.Gu., R.G., B.M.H., H.B., M.Gr., K.M.G.); Metabolic Unit, Department of Clinical Chemistry, Vrije Universiteit (VU) University Medical Center, Amsterdam, The Netherlands (E.E.W.J., C.J., B.M.H.); Department of Biochemistry, Cardiovascular Research Institute, Medical Faculty, Erasmus University, Rotterdam, The Netherlands (B.M.H.); Novartis Pharma Inc., Basel, Switzerland (W.F.); and Department of Pediatrics, Division of Neurology and The Program in Brain and Behavior, Faculty of Medicine, Hospital for Sick Children, Toronto, Ontario, Canada (O.C.S.)

Therapeutic intervention for human succinic semialdehyde dehydrogenase (SSADH) deficiency (-hydroxybutyric aciduria) has been limited to vigabatrin (VGB). Pharmacologically, VGB should be highly effective due to 4-aminobutyrate-transaminase (GABA-transaminase) inhibition, lowering succinic semialdehyde and, thereby, -hydroxybutyric acid (GHB) levels. Unfortunately, clinical efficacy has been limited. Because GHB possesses a number of potential receptor interactions, we addressed the hypothesis that antagonism of these interactions in mice with SSADH deficiency could lead to the development of novel treatment strategies for human patients. SSADH-deficient mice have significantly elevated tissue GHB levels, are neurologically impaired, and die within 4 weeks postnatally. In the current report, we compared oral versus intraperitoneal administration of VGB, CGP 35348 [3-aminopropyl(diethoxymethyl)phosphinic acid, a GABA_B receptor antagonist], and the nonprotein amino acid taurine in rescue of SSADH-deficient mice from early death. In addition, we assessed the efficacy of the specific GHB receptor antagonist NCS-382 (6,7,8,9-tetrahydro-5-[H]benzocycloheptene-5-ol-6-ylideneacetic acid) using i.p. administration. All interventions led to significant lifespan extension (22-61%), with NCS-382 being most effective (50-61% survival). To explore the limited human clinical efficacy of VGB, we measured brain GHB and -aminobutyric acid (GABA) levels in SSADH-deficient mice receiving VGB. Whereas high-dose VGB led to the expected elevation of brain GABA, we found no parallel decrease in GHB levels. Our data indicate that, at a minimum, GHB and GABA_B receptors are involved in the pathophysiology of SSADH deficiency. We conclude that taurine and NCS-382 may have therapeutic relevance in human SSADH deficiency and that the poor clinical efficacy of VGB in this disease may relate to an inability to decrease brain GHB concentrations.