Gibson Laboratory
Research Interests
Our laboratory broadly examines heritable disorders of human metabolism, also defined as inborn errors of metabolism.  We study several autosomal-recessive disorders (described below), and the focus is on understanding the pathophysiology through knockout of the corresponding gene in the mouse and characterization of the clinical and biochemical phenotype.  The ultimate objective is to develop novel treatment approaches for patients utilizing preclinical data gathered in animal models. 

SSADH Deficiency
Patients with heritable succinate semialdehyde dehydrogenase (SSADH) deficiency have been a focus of the Gibson laboratory for more than 25 years.  SSADH deficiency is a rare, heritable disorder of GABA degradation in which two neuromodulators accumulate, GABA (the major inhibitory neurotransmitter in mammalian central nervous system), and the GABA analogue GHB (gamma-hydroxybutyric acid).  The latter is an enigmatic compound that accumulates to minor levels in normal mammalian brain, is an expanding drug of abuse, and is currently used as a class III clinical intervention in the treatment of narcolepsy. 

Fig. 1.  Schematic of GABA degradation and metabolites accumulating (arrows adjacent to metabolites) in Aldh5a1 deficiency (depicted by cross-hatched box).  Abbreviations: SSA, succinate semialdehyde; -KG, -ketoglutarate; D-2-HG, D-2-hydroxyglutarate; DHHA, 4,5-dihydroxyhexanoic acid; TCA, tricarboxylic acid.

Deletion of the SSADH gene (also known as the aldehyde dehydrogenase 5a1 gene, or Aldh5a1) in mice leads to a severe phenotype with early lethality (at about 4 weeks) from status epilepticus.  Early lethality has offered an opportunity in the mouse to characterize a number of potential preclinical interventions that may generate important pharmacological data for pilot trials in human patients.  Two compounds, namely taurine (a non-physiological amino acid) and SGS-742 (a GABA(B) receptor antagonist) have shown efficacy in the animal model and are currently in use in pilot clinical trials for patients.  In addition, exhaustive analyses of the pathophysiology of the murine model has provided fundamental new insight into parallel processes in the human disorder.

MSUD (Maple syrup urine disease)
MSUD is one of the prototypical amino acidurias, caused by an inherited deficiency of the branched chain ketoacid dehydrogenase (BCKDH) complex that is necessary for the early metabolism of the branched chain amino  acids, leucine, valine and isoleucine.  Recently, murine models of this disorder have been developed, and these animals represent relevant phenocopies of the corresponding human disorder.  Treatment of MSUD is represented by a lifelong adherence to a diet devoid of the branched chain amino acids, which is facilitated by protein restriction.  A special dietary formulation is utilized for patients that is restricted in the appropriate amino acids, but this intervention is unpalatable and adherence to diet is challenging.  Patients who suffer crises associated with high blood levels of branched chain amino acids can progress rapidly to coma that is associated with high central nervous system levels of leucine, the major offending species.
Our laboratory, in collaboration with several others, has begun to explore the efficacy of cell therapy in MSUD.  This approach utilizes exogenous hepatocytes as a vehicle to repopulate the host MSUD liver with functional hepatocytes carrying a normal complement of functional BCKDH activity.  Preliminary studies have been very encouraging with this approach, and it has been shown that repopulation of the host murine MSUD liver with ~3% of exogenous hepatocytes can result in an approximate 70% decrease in the level of circulating leucine and other branched chain amino acids.  In addition to this, our laboratory has shown that several neurotransmitter intermediates are detrimentally altered in MSUD mice, and that hepatocyte repopulation leads to significant improvement of these abnormalities.  Thus, hepatocyte intervention may have an important role in the long term treatment of human MSUD.

Fig. 2. Oxidative degradation of the BCAAs leucine, isoleucine, and valine. The transamination of BCAA is catalyzed by a single branched-chain aminotransferase (reaction 1) that exists as both the cytosolic and mitochondrial isoforms. The oxidative decarboxylation of BCKAs is catalyzed by the single mitochondrial branched-chain -ketoacid dehydrogenase complex (BCKD=BCKDH; reaction 2). The metabolic block at the second reaction results in MSUD.

Phenylketonuria
Phenylketonuria represents another of the primary amino acidurias, and the most well known of the inherited disorders of metabolism.  Phenylketonuria is the result of an inherited deficiency of phenylalanine hydroxylase (PAH), a primarily hepatic enzyme important in the production of tyrosine.  Dietary restriction of phenylalanine is the treatment of choice, and the seminal work of Dr. Robert Guthrie in the 1960s led to the development of newborn screening in blood to detect phenylketonuria (by measurement of phenylalanine levels utilizing a bacterial inhibition assay).  Early implementation of a phenylalanine restricted diet, linked to rapid newborn detection, prevented the documented mental retardation syndrome associated with high circulating levels of phenylalanine.
A murine model of phenylketonuria is available, and our laboratory has begun to explore the neuropathology associated with this disorder.  In particular, we are interested in the effects of altered phenylalanine metabolism on monoamine neurotransmitters, namely dopamine (DA) and serotonin (or 5-HT, 5-hydroxytryptamine).  Tyrosine and tryptophan are the immediate precursors of these important monoamines, which control critical processes in mammals such as movement, speech, body temperature, mood and anxiety.  We have found significant alterations of monoamine levels in the neural tissue of untreated PKU mice, and our laboratory continues to explore mechanisms by which these alterations can be corrected.  These investigations represent important and essential preclinical evaluations that are needed before pilot trials with new interventions are attempted in human PKU.


Fig. 3.  Abbreviated schematic diagram of reactions involved in the metabolism of the monoamine neurotransmitters, dopamine and serotonin (not all steps are shown).  Abbreviations: L-DOPA, L-dihydroxyphenylalanine; 5-HTP, 5-hydroxytryptophan; ALAAD, aromatic L-amino acid decarboxylase; DOPAC, 3,4-dihydroxyphenylacetic acid; HVA, homovanillic acid; 3-MT, 3-methoxytyramine; 5-HIAA, 5-hydroxyindoleacetic acid.

Mevalonate Kinase Deficiency
Mevalonate kinase deficiency (MKD) is an inborn error of cholesterol biosynthesis, and the only defect known in the pre-squalene portion of the cholesterol biosynthetic pathway.  Our laboratory was responsible for identification of this disease in 1986.  Please see the laboratory of Dr. Elizabeth Hager (Biological Sciences) for a more comprehensive discussion of MKD.

Recent publications
(IF=Impact Factor;www.isiknowledge.com)

Knerr I., Gibson K.M., Jakobs C., Pearl P.L. (2008) Neuropsychiatric morbidity in adolescent and adult succinic semialdehyde dehydrogenase (SSADH) deficiency patients. CNS Spectrums 13: 598-605. [I.F.=2.222]

Nylen K., Perez-Velazquez J.L., Likhodii S.S., Cortez M.A., Shen L., Leshchenko Y., Khosrow A., Gibson K.M., Burnham W.M., Snead III O.C. (2008) A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype. Exper Neurol. 210: 449-457  [I.F.=3.982]

Drasbek K.R., Vardya I., Delenclos M., Gibson K.M., Jensen K (2008) SSADH deficiency leads to elevated extracellular GABA levels and increased GABAergic neurotransmissionin the mouse cerebral cortex.  J Inherit Metab Dis 31: 662-668 [I.F.=1.668]

Stewart L.S., Nylen K.J., Persinger M.A., Cortez M.A., Gibson K.M., Snead O.C. (2008)  Circadian distribution of generalized tonic-clonic seizures associated with murine succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism.  Epilepsy Behav 13: 290-294 [I.F.=2.095]

Jansen E.E.W., Struys E.A., Jakobs C., Hager E.J., Snead O.C., Gibson K.M. (2008) Neurotransmitter alterations in embryonic succinate semialdehyde dehydrogenase (SSADH) deficiency suggest a heightened excitatory state during development.  BMC Developmental Biology 8:112 [I.F.=3.337]

Malaspina P., Picklo M.J., Jakobs C., Snead O.C., Gibson K.M (2009) Comparative genomics of aldehyde dehydrogenase 5a1 (succinate semialdehyde dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiency.   Hum Genomics 3:106-20.

Pearl PL, Gibson KM, Cortez MA, Wu Y, Carter Snead O 3rd, Knerr I, Forester K, Pettiford JM, Jakobs C, Theodore WH (2009) Succinic semialdehyde dehydrogenase deficiency: lessons from mice and men.  J Inherit Metab Dis Jan 28 [Epub ahead of print] [I.F.=1.668]

Bonilla Guerrero R, Wolfe LA, Payne N, Tortorelli S, Matern D, Rinaldo P, Gavrilov D, Melan M, He M, Steinberg SJ, Raymond GV, Vockley J, Gibson KM (2008) Essential fatty acid profiling for routine nutritional assessment unmasks adrenoleukodystrophy in an infant with isovaleric academia.  J Inherit Metab Dis Dec 16 [Epub ahead of print]  [I.F.=1.668]

Nylen K, Velazquez JL, Sayed V, Gibson KM, Burnham WM, Snead OC 3rd (2009)  The effects of a ketogenic diet on ATP concentrations and the number of hippocampal mitochondria in Aldh5a1(-/-) mice.  Biochim Biophys Acta 1790: 208-212.[I.F.=2.37].

Goodwin AK, Brown PR, Jansen EE, Jakobs C, Gibson KM, Weerts EM (2009) Behavioral effects and pharmacokinetics of gamma-hydroxybutyrate (GHB) precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) in baboons. Psychopharmacology (Berl) Feb 6 [Epub ahead of print][I.F.=3.561]

Pearl P.L., Gibson K.M.,  Quezado, Z., Dustin, I., Taylor, J., Trzcinski, S., Schreiber, J., Forester, K., Reeves-Tyer, P., Liew, C., Shamim, S., Herscovitch, P., Carson, R., Butman, J., Theodore W.H (2009) Decreased GABA-A binding on FMZ-PET in gamma-hydroxybutyric aciduria..  Neurology, in press [I.F.=6.014].

Wickenhagen WV, Salomons GS, Gibson KM, Jakobs C, Struys EA (2009).  Measurement of D-2-hydroxyglutarate dehydrogenase activity in cell homogenates derived from D-2-hydroxyglutaric aciduria patients. J Inherit Metab Dis 32: 264-268 [I.F.=1.668].

Skvorak KJ, Paul HS, Dorko K, Marongiu F, Ellis E, Chace D, Ferguson C, Gibson KM, Homanics GE, Strom SC (2009) Hepatocyte transplantation improves phenotype and extends survival in a murine model of intermediate maple syrup urine disease.  Molec Ther 17: 1266-1273 [I.F.=5.862].

Di Rosa G, Malaspina P, Blasi P, Dionisi-Vici C, Rizzo C, Tortorella G, Crutchfield SR, Gibson KM (2009) Visual evoked potentials in succinate semialdehyde dehydrogenase (SSADH) deficiency.  J Inherit Metab Dis May 30 [Epub ahead of print][I.F.=1.668].

Sepulveda JL, Tanhehco YC, Frey M, Guo L, Cropcho LJ, Gibson KM, Blair HC (2009) Variation in human erythrocyte membrane unsaturated fatty acids: correlation with vascular disease.  Arch Pathol Lab Med, in press [I.F.=1.806].

Pearl PL, Shamim S, Theodore WH, Gibson KM, Forester K, Dustin I, Reeves-Tyer P, Jakobs C, Sata S (2009) Sleep and polysomnographic abnormalities in succinic semialdehyde dehydrogenase (SSADH) deficiency.  Sleep, in press [I.F.=4.34].

Links:
www.ncbi.nlm.nih.gov (PubMed, complete citations Gibson KM)
www.pndassoc.org (Pediatric Neurotransmitter Disease Association)

Current grant support:
(1) 5 R01 NS40270 (PI: K. Michael Gibson) 01/15/06 – 12/31/09 "Murine Knockout Model of 4-Hydroxybutyric Aciduria"
The major goals of this project: 1) to develop and characterize the knockout model of succinic semialdehyde dehydrogenase (SSADH) deficiency in the murine system. 2) to characterize the EEG findings and behavioral anomalies of SSADH-deficient mice, and their susceptibility to absence seizures in comparison with wild-type mice; and 3) to explore novel therapeutic and gene therapy paradigms in SSADH deficient mice as a springboard for developing preclinical treatment regimens for human SSADH deficiency.

(2) (PI: K. Michael Gibson) 05/01/07 - 09/30/09 Pediatric Neurotransmitter Disease Association "Hepatocyte Repopulation in Gamma-Hydroxybutyric Aciduria”
The major goal of this project is to assess the potential of hepatocyte repopulation to correct heritable SSADH deficiency in mice, as an essential prelude to the development of novel preclinical treatment paradigms for patients.

(3) DK078775 (PI: Gerard Vockley) 12/01/07-11/30/11 “Inborn Errors of Long Chain Fat Metabolism” 
The goal of this study is to characterize the physiological roles of LCAD, VLCAD, and ACD9 and explore the ramifications of genetic deficiencies of these enzymes in humans and mouse models.

(4) R01 DA14919 (PI: Elise M. Weerts)  04/1/07 – 12/31/11 "Behavioral Pharmacology of GHB Physical Dependence"
The objectives of these studies are to understand the potential for abuse and addiction for GHB in a primate model, and to compare these abuse characteristics with the GHB-progenitors gamma-butyrolactone and 1,4-butanediol.

(5) R03 HD57564(PI: K. Michael Gibson) 4/01/08 – 3/31/10 “Murine Knockout Model of Mevalonic Aciduria”
The goals of this project are to understand embryologic malformations in a null model of mevalonate kinase deficiency in the mouse, and examine the potential to bypass early lethality using knock-in methodology.

(6) R01 HD58553 (PI: K. Michael Gibson) 12/01/08 – 11/30/13 “Novel Treatment and Screening Strategies in Heritable Gamma-Hydroxybutyric Aciduria”
The long term goals are to define an effective treatment strategy for patients and springboard that treatment into expanded newborn screening for SSADH deficiency.