Milestones

2015 to present

2019 – the Center for Disease Control and Prevention (CDC) has issued an ICD-10-CM code E72.81 Disorders of gamma aminobutyric acid metabolism, specifically for SSADH.  This will allow medical professionals to code a patient visit for SSADH. 


2018 – Dr. Gibson was awarded $686,980 from a grant through the NIH to conduct a Natural History Study which will be of great value for future research and for the FDA drug approval process. The Natural History Study will aim to determine the natural evolution and the clinical presentation of SSADH with yearly neurological and neuropsychiatric assessments.



2018
– Dr. Gibson was awarded $686,980 from a grant through the NIH to conduct a Natural History Study which will be of great value for future research and for the FDA drug approval process. The Natural History Study will aim to determine the natural evolution and the clinical presentation of SSADH with yearly neurological and neuropsychiatric assessments.

SSADH has a broad spectrum of symptoms and severity varies greatly among patients, even within the same family. Our hope is that the Natural History Study and the complimentary Biorepository will help to correlate clinical severity with prior-years predictor levels to better determine the natural evolution of SSADH.


2018 – SSADH Association has awarded $12,000 to Ritva Tikkanen, MD, PhD from Justus-Liebig Universität Gießen, Germany to create molecular consequences of SSADH mutations allowing for mutation specific therapies. Dr. Tikkanen will be using the SSADH stem cell lines created at Boston Children’s Hospital. 



2018
– SSADH Association committed $10,000 to maintain a Backup SSADH Mice Colony at JEX Services to ensure the availability of SSADH Mice should something happen to the existing colony at Washington State University, preventing any lapse in research due to the lack of SSADH mice.


2018 – SSADH Association awarded $125,000 to Phillip Pearl, MD & Mustafa Sahin MD, PhD at Boston Children’s Hospital and Harvard Medical School in addition to an anonymous $175,000 donation on behalf of the Boston Children’s Hospital Trust.  This project will be a continuation of our initial funding from 2015 to create SSADH stem cells and heterozygous controlled GABA’ergic iPSC lines. The goal of this phase will be to use the patient iPSC neurons to screen for novel therapeutic approaches to treatments.


2017 – SSADH Association committed $10,000 to establish a Backup SSADH Mice Colony at JEX Services to ensure the availability of SSADH Mice should something happen to the existing colony at Washington State University, preventing any lapse in research due to the lack of SSADH mice.


2017 – SSADH Association awarded $305,616 to K. Michael Gibson, PhD, FACMG at Washington State University for the SSADH Biorepository project which aims at creating a biobank where biospecimens and matching clinical data are collected longitudinally from all interested: patients, siblings and family members, unaffected, age-matched control individuals. The Biorepository will be created over the next five years with the following team:  Drs. Gibson and Roullet, (WSU), Dr. Pearl (BCH), Dr. Opladen (iNTD, Heidelberg, Germany) and the SSADH Association.


2016 – SSADH Association committed $10,000 to kick off a Natural History Study with the US medical team of Phil Pearl, MD, (Boston Children's Hospital), Jean-Baptiste Roullet, PhD, and Mike Gibson, PhD, FACMG, (both from WSU), together with Evangeline Wassmer, PhD (UK), Thomas Opladen, MD, (Germany) and Garcia-Cazorla, PhD, (Spain) will work with the SSADH Association on a grant proposal to support a multi-year (5+) and multi-site natural history study of SSADH patients.


2016 – SSADH Association awarded $100,000 to Phil Pearl, MD & Robin Kleiman, PhD, to fund a one year research grant in conjunction with Boston Children’s Hospital. The objective of this project is to develop an in vitro disease model of SSADH Deficiency from patient iPSC lines differentiated into GABAergic neurons that will support phenotypic drug screening.


2016 – Preclinical NCS-382 studies; vigabatrin ocular toxicity in SSADH


2015 – Investigation of the immunological response in SSADH cells by Karen Newell-Rogers, PhD at Texas A&M to understand the alterations in metabolism and immunity using the SSADH mouse model.


2015 – Evaluation of Metabolites in SSADH Urine is being studied by Dr. Kara Vogel at Washington State University to explore possibilities for SSADH patients.


2015 – SSADH Association awarded $5,000 was awarded to Kestutis G. Bendinskas, PhD at SUNY-Oswego to develop an easy to use field colorimetric assay screen to detect the biomarker for SSADH deficiency gamma hydroxybutyric acid (GHB), in either urine or saliva to screen candidates. 


2015 – SSADH Association awarded $100,000 to K. Michael Gibson, PhD, FACMG at Washington State University to garner efficacy data in the SSADH deficient animal model to form the framework for the Investigational New Drug Application with the NIH for the use of compounds NCS-382 and HOCPCA.


2015 – SSADH Association awarded $158,950 to the University of California, San Diego to determine if the induction of autophagy by rapamycin would remove surplus organelles, thus reducing oxidative stress and restoring cellular homeostasis which may lead to potential treatments for SSADH deficiency.


2010 to 2014

2010 – Dr. Gibson is awarded a $50,000 grant from the PND Association towards SSADH deficiency entitled “Efficacy of Ornithine Alpha Ketoglutarate Intervention in SSADHD“.


2011 – The NIH receives a $45,000 grant from the SSADH Association towards the encapsulation of
SGS-742, a medication that will be studied in a NIH Clinical Research Study.


2012 – Human GABABR dysfunction using transcranial magnetic stimulation


2013 – Testing of an experimental drug’s effectiveness on SSADH has been funded by a $743,974 grant from the National Institutes of Health to Dr. Gibson Washington State University professor.


2013 – SSADH Association awards $79,500 Fellowship Research Grant to Ronak Lakhani, PhD at the University of California, San Diego to understand the use of rapamycin and other autophagy-inducing drugs for treating SSADH deficiency.


2014 – NIH Clinical Trail of Taurine to combat the impact of SSADH complete.


2014 – NIH Phase 2 Clinical Trial of SGS-742 Therapy Recruiting SSADHD Patients


2014 – SSADH Association awards an additional One Year Research Grant to Ronak Lakhani, PhD at the University of California, San Diego to determine if the induction of autophagy by Rapamycin would remove surplus organelles, thus reducing oxidative stress and restoring cellular homeostasis which may lead to potential treatments for SSADH Deficiency.

2005 to 2009

2005 – NIH Clinical Research Study “Cortical Excitability in SSADHD Patients”


2005 – NIH Clinical Research Study “PET Imaging of GABA Receptors in Succinic Semialdehyde Dehydrogenase Deficiency”


2006 – NIH Clinical Research Study “Taurine and its effect on SSADH patients”


2008 – Identification of metabolic disruptions in embryonic KO mice


2008 – Rescue of KO mice with the ketogenic diet


2009 – Human GABABR dysfunction using 11C-flumazenil binding


2009 – Crystal structure of human SSADHD; Dynamic Catalytic Loop


2009 – Efficacy of SGS-742 (GABABR antagonist) in KO mouse

2000 to 2004

2000 – Dr. Gibson is awarded a $6,000 grant from the PND Association contributing towards his GHB Research Fund.


2001 – Dr. Gibson developed a murine knockout (KO) model of SSADHD.


2003 – Compilation of 27 disease-associated mutations in SSADHD.


2004 – Dr. Phil Pearl is awarded a $30,000 grant from the PND Association to add a research fellowship towards developing an SSADH clinical profile and database.


2004 to 2006 – Definition of KO mouse seizure profile; GABABR / GABAAR abnormalities


2004 to 2005 – Dr. Gibson asked to present the 10th Annual Komrower Commemorative Lecture, the key invited talk, at the Annual Meeting of the Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Meeting in Amsterdam, with a talk entitled “Gamma-Hydroxybutyric Aciduria: A Biochemist’s Education from a Heritable Disorder of GABA Metabolism”

1995 to 1999

1995 – Composite clones encoding mature rat brain SSADHD predicted a protein with 488 amino acids, consistent with Dr. Gibson’s purified protein data. The cDNA clones were confirmed by expression of enzyme activity in bacteria, and the human gene was mapped to chromosome 6p22, spanning some 38 kb of genomic DNA.


1995 to 1998 – Molecular cloning of ALDH5A1 gene; Identification of Mutations


1997 – Genotype/phenotype correlations in 23 patients; case histories


1999 to 2009 – Dr. Mike Gibson and Dr. O. Carter Snead are funded continuously by the NIH for their R01 studies on the mouse model of 4-hydroxybutyric aciduria (project entitled “Pathophysiology and Treatment of Inherited Gamma-Hydroxybutyric Aciduria in the Mouse”.

1990 to 1994

1990 – Dr. Gibson employs a fluorometric assay and isotope dilution method for GHB which facilitated prenatal diagnoses, using parallel investigations of metaboloites in amniotic fluid with enzyme measurement in amniocytes and chorionic villus tissue.


1992 – Dr. Gibson began to purify mammalian SSADHD with the goal of cloning the gene and determining whether patients harboured mutations. His laboratory developed a new purification scheme for isolation of rat brain SSADHD, combining ion-exchange and affinity chromatography steps to purify the protein to apparent homogeneity.


1993 – Prenatal Detection of SSADHD; Identification of CNS Enzyme Defect

1985 to 1989

1987 – Dr. Garry Brown identifies DHHA in the urine of SSADHD patients using GCMS


1985 to 1990 – Dr. Gibson focuses his time on identifying patients, developing improved assay methods for enzyme and metabolite quantitation, performing the infrequent prenatal diagnosis, and beginning to outline the cloning of mammalian SSADHD.

1980 to 1984

1981 – Dr. Cornelis Jakobs identified a mentally retarded boy with minimal language development. Urine organic acid analysis of this child revealed an increased quantity of gamma hydroxybutyric acid (GHB), a compound that had not previously been identified in human urine. Dr. Jakobs postulated that this child had an inherited defect in the metabolism of GABA.


1982 – Dr. K. Michael Gibson alters career path to pursue documenting the enzyme defect in Dr. Jakob’s patient. During this time, Dr. Gibson drew his own blood to look for SSADH activity in white-cell extracts which provided a method and a peripheral tissue source in which to document the enzyme defect in the first three SSADH patients, and began a long journey in the investigation of this rare disorder.