Transcript Gibson-Historical Timeline

Historical Timeline of SSADH
Deficiency
Mike Gibson
Experimental and Systems Pharmacology
College of Pharmacy, Washington State University
……”Nature is nowhere accustomed more openly to
display her secret mysteries than in cases where she
shows traces of her workings apart from the beaten
path; nor is there any better way to advance the proper
practice of medicine than to give our minds to the
discovery of the usual law of Nature by careful
investigation of cases of rarer forms of disease”
-------William Harvey (1657)
Jakobs C, Bojasch M, Mönch E, Rating D, Siemes H, Hanefeld F. Urinary
excretion of gamma-hydroxybutyric acid in a patient with neurological
abnormalities. The probability of a new inborn error of metabolism.
Clin Chim Acta. 1981 Apr 9;111(2-3):169-78.
“Metabolic Understanding in the 1980-1990s”
Landmarks in SSADHD Research
Year(s)
Achievement(s)
Citation(s)
1981-1983
1992
1993
1993
1995-1998
1997
2001-2002
2003
2004-2006
Biochemical (GHB)/Enzymatic Identification of SSADHD
Purification of Mammalian SSADHD
Prenatal Detection of SSADHD; Identification of CNS Enzyme Defect
Jakobs et al 1981; Gibson et al 1983
Chambliss and Gibson 1992
Jakobs et al 1993; Chambliss et al
Molecular Cloning of ALDH5A1 Gene; Identification of Mutations
Genotype/Phenotype Correlations in 23 Patients: Case Histories
Development of Murine Knockout Mouse-Pharmacological Rescue
Compilation of 27 Disease-Associated Mutations in SSADHD
Definition of KO Mouse Seizure Profile; GABABR/GABAAR Abnormalities
2008
2008
2009
2009
2009
2012
2014
2014
2014, 2015
Identification of Metabolic Disruptions in Embryonic KO Mice
Rescue of KO Mice with the Ketogenic Diet
Human GABAAR Dysfunction using 11C-Flumazenil Binding
Crystal Structure of Human SSADH; “Dynamic Catalytic Loop”
Efficacy of SGS-742 (GABABR antagonist) in KO Mouse
Human GABABR Dysfunction using Transcranial Magnetic Stimulation
Clinical Trial of Taurine Intervention in SSADHD (completed)a
Clinical Trial of SGS-742 Intervention in SSADHD (ongoing)
Identification of GABA Role in Autophagy; Rapalog Therapeutics
Chambliss et al 1995; 1998
Gibson et al 1997
Hogema et al 2001; Gupta et al 2002
Akaboshi et al 2003
Cortez et al 2004; Buzzi et al 2006;
Wu et al 2006
Jansen et al 2008
Nylen et al 2008
Pearl et al 2009
Kim et al 2009
Pearl et al 2011
Reis et al 2012
Pearl et al 2014
(unpublished)
Lakhani et al 2014; Vogel et al 2015
•
•
•
•
Taurine
CGP-35348
Vigabatrin
NCS-382
• Ketogenic Diet
Metabolic Insights Today……….
HOCPCA
GABAB Receptor
(cAMP; metabotropic)
SGS-742
NCS-382
??
GHB Receptor
(cAMP; metabotropic)
??
Succinate
GABAA Receptor
(Cl- channel)
Diclofenac
SSADH
Dopaminergic
pathways (release)
GABA-T
GABA
Autophagy,
mitophagy
Rapalog targets
SSA
GHB
AR-C155858
(GHB transport)
Vigabatrin
D-2-hydroxyglutaric acid?
4,5-dihydroxyhexanoic acid?
Take home lessons after 35
years of research……..
“The more you learn, the more you begin to
realize you don’t know”
“Monogenic disorders are anything but
monogenic”
Acknowledgements
• Dr. Kara Vogel
• Dr. Garrett Ainslie
• Dr. Cornelis Jakobs
• Dr. William Nyhan
• Dr. Lawrence Sweetman
• SSADHD Patients
• SSADHD Parents
• NIH R01 NS82286
• NIH R21 NS85369
• Aldeyra Therapeutics
• SSADH Association
• U54 DK 83916