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

Wolfe LA, He M, Vockley J, Payne N, Rhead W, Hoppel C, Spector E, Gernert K, Gibson KM., Novel ETF dehydrogenase mutations in a patient with mild glutaric aciduria type II and complex II-III deficiency in liver and muscle. J Inherit Metab Dis. 2010 Nov 19.

Kim KJ, Pearl P, Jensen K, Snead OC, Malaspina P, Jakobs C, Gibson KM., Succinic Semialdehyde Dehydrogenase (SSADH) : Biochemical-Molecular-Clinical Disease Mechanisms, Redox Regulation and Functional Significance. Antioxid Redox Signal. 2010 Oct 25.

Wamelink MM, Roos B, Jansen EE, Mulder MF, Gibson KM, Jakobs C., 4-Hydroxybutyric aciduria associated with catheter usage: A diagnostic pitfall in the identification of SSADH deficiency.Mol Genet Metab. 2011 Feb;102(2):216-7. Epub 2010 Oct 7.PMID: 20965758

Kranendijk M, Struys EA, van Schaftingen E, Gibson KM, Kanhai WA, van der Knaap MS, Amiel J, Buist NR, Das AM, de Klerk JB, Feigenbaum AS, Grange DK, Hofstede FC, Holme E, Kirk EP, Korman SH, Morava E, Morris A, Smeitink J, Sukhai RN, Vallance H, Jakobs C, Salomons GS., IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science. 2010 Oct 15;330(6002):336.

Bi W, Bi Y, Xue P, Zhang Y, Gao X, Wang Z, Li M, Baudy-Floc'h M, Ngerebara N, Gibson KM, Bi L., Synthesis and characterization of novel indole derivatives reveal improved therapeutic agents for treatment of ischemia/reperfusion (I/R) injury. J Med Chem. 2010 Sep 23;53(18):6763-7.PMID: 20731361

Vardya I, Drasbek KR, Gibson KM, Jensen K., Plasticity of postsynaptic, but not presynaptic, GABAB receptors in SSADH deficient mice. Exp Neurol. 2010 Sep;225(1):114-22. Epub 2010 Jun 4.PMID: 20570675

Harding CO, Gibson KM., Therapeutic liver repopulation for phenylketonuria. J Inherit Metab Dis. 2010 Dec;33(6):681-7. Epub 2010 May 22.PMID: 20495959

Acosta MT, Munasinghe J, Pearl PL, Gupta M, Finegersh A, Gibson KM, Theodore WH., Cerebellar atrophy in human and murine succinic semialdehyde dehydrogenase deficiency. J Child Neurol. 2010 Dec;25(12):1457-61. Epub 2010 May 5.PMID: 20445195

Dósa Z, Nieto-Gonzalez JL, Korshoej AR, Gibson KM, Jensen K., Effect of gene dosage on single-cell hippocampal electrophysiology in a murine model of SSADH deficiency (gamma-hydroxybutyric aciduria). Epilepsy Res. 2010 Jun;90(1-2):39-46. Epub 2010 Apr 3.PMID: 20363598

Knerr I, Gibson KM, Murdoch G, Salomons GS, Jakobs C, Combs S, Pearl PL., Neuropathology in succinic semialdehyde dehydrogenase deficiency. Pediatr Neurol. 2010 Apr;42(4):255-8.PMID: 20304328

Pearl PL, Reehal T, Drillings I, Gibson KM., Succinic Semialdehyde Dehydrogenase Deficiency . In: Pagon RA, Bird TC, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993- 2004 May 5 [updated 2010 Oct 5].PMID: 20301374

Sepulveda JL, Tanhehco YC, Frey M, Guo L, Cropcho LJ, Gibson KM, Blair HC., Variation in human erythrocyte membrane unsaturated Fatty acids: correlation with cardiovascular disease. Arch Pathol Lab Med. 2010 Jan;134(1):73-80.PMID: 20073608

Tsuji M, Aida N, Obata T, Tomiyasu M, Furuya N, Kurosawa K, Errami A, Gibson KM, Salomons GS, Jakobs C, Osaka H., A new case of GABA transaminase deficiency facilitated by proton MR spectroscopy. J Inherit Metab Dis. 2010 Feb;33(1):85-90. Epub 2010 Jan 6.PMID: 20052547

http://www.ncbi.nlm.nih.gov/pubmed?term=gibson%20km

Current grant support:

Ongoing Research Support
2 R01 NS40270, K. Michael Gibson, Ph.D. (P.I.)   1/15/06 - 12/31/10
NIH/NINDS "Murine Knockout Model of 4-Hydroxybutyric Aciduria"
Objectives are to examine novel pharmacotherapeutics in SSADH-/- mice as preclinical treatment paradigms,  to examine the mechanisms of seizure transition, and to examine liver repopulation as a mechanism of long-term correction of disease. (currently in no-cost extension)

1 R03 HD57564, K. Michael Gibson, Ph.D. (P.I.)      5/1/08-11/30/10
NIH/NICHD “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.  (currently in no-cost extension)

1 R01 HD58553, K. Michael Gibson, Ph.D. (P.I.)    12/1/09-11/30/14
NIH/NICHD “Novel Treatment and Screening Strategies in Heritable Gamma-Hydroxybutyric Aciduria”
The goals of this study are to characterize the antiepileptic features of the GABA(B) receptor antagonist SGS-742 in Aldh5a1 null mice, perform a limited clinical trial of SGS-742 in Aldh5a1 patients, and develop a newborn screening method for detection of Aldh5a1 deficiency.

NIH Bench to Bedside, K. Michael Gibson, Ph.D. (extramural investigator) 7/1/09-6/30/2011
Supplement to HD 58553 “Therapeutic Efficacy of SGS-742 in Succinic Semialdehyde Dehydrogenase Deficiency”
The NIH Bench to Bedside clinical program partners an NIH intramural investigator (Dr. William Theodore, PI) with an extramural, NIH-funded investigator to undertake a clinical trial.  In this instance, Drs. Theodore and Gibson will examine the therapeutic benefits of the GABA(B) receptor antagonist, SGS-742, in both patients and mice with inherited succinic semialdehyde dehydrogenase deficiency.

Robert D. Steiner, MD (PI) (PI: Gibson, subcontract)     10/1/09 – 9/30/14
Oregon Health & Science University 
“Sterol and Isoprenoid Rare (STAIR) Diseases Clinical Research Consortium”
A sterol and isoprenoid disease consortium has been established as part of the Rare Diseases Clinical Research Network (RDCRN).  The subcontract PI (Gibson) oversees a component of this project, evaluating physiological fluids (blood, urine) obtained from patients with hyper IgD syndrome (HIDS).  The goal is to identify novel biomarkers in HIDS patients, for eventual use as surrogate outcome measures during pilot and phase II clinical trials.

K. Michael Gibson, PhD (P.I.)    4/01/10 – 03/31/11 
Pediatric Neurotransmitter Disease Association   
“Therapeutic Efficacy of OAK Intervention in 4-Hydroxybutyric Aciduria”
The objective of this research is to examine the potential for long-term bioenergetic improvements and amelioration of  disease manifestations in SSADH-deficient mice using oral intervention with OAK (ornithine alphaketoglutarate).

Completed Research Support

K. Michael Gibson, PhD (P.I.)    4/01/07 – 03/31/09 
Pediatric Neurotransmitter Disease Association   
“Hepatocyte Repopulation in 4-Hydroxybutyric Aciduria”
The objective of this research is to examine the potential for long-term amelioration of disease in SSADH-deficient mice using engraftment of normal hepatocytes into liver.

K. Michael Gibson, PhD (P.I.)    1/01/08 – 12/31/08 
Research Advisory Committee (RAC)-Children’s Hospital of Pittsburgh (Seed Grant)   
“Mechanisms of Ketogenic Diet Efficacy in the Aldh5a1-/- Epileptic Mouse Model”
The objective of this research is to examine the mechanisms of efficacy for ketogenic diet intervention in a murine epileptic model, and potentially to springboard those studies to a better understanding of epilepsy intervention.

1 R01 DA14919, Elise M. Weerts, Ph.D. (P.I.; Gibson subcontract) 2/1/08-1/31/13
NIH/NIDA “Behaviorial 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.