SPOKANE, Wash. – Further testing of an experimental drug’s effectiveness on an inherited disorder with characteristics of autism and epilepsy has been funded by a $743,974 grant from the National Institutes of Health to a Washington State University professor.

Dr. K. Michael Gibson, head of the clinical pharmacology section in WSU’s College of Pharmacy, and three other collaborators already have tested the effectiveness of an amino acid for the disorder, and will use a similar clinical trial approach to test the experimental drug SGS742.

The researchers also will make a recommendation to the NIH as to whether SGS742 has sufficient promise to warrant further investment. The drug has been around since the 1990s and showed some promise in the past for memory improvement, but was not further explored for use in Alzheimer’s Disease.

The drug selectively competes with a neurotransmitter receptor in the brain that is intricately involved in the inherited disorder succinic semialdehyde dehydrogenase (SSADH) deficiency, which Gibson has been studying for more than 30 years since discovering the primary enzyme defect in his doctoral work at the University of California at San Diego.

Gibson is a new researcher at WSU and was recruited from Michigan Technological University to the College of Pharmacy in July 2012 with the help of a grant from the Health Sciences and Services Authority of Spokane County.

SSADH deficiency causes a variety of neurological problems, including developmental delay, intellectual disability, decreased muscle tone, seizures, difficulty coordinating movements, decreased reflexes and behavioral problems such as sleep disturbance, hyperactivity, difficulty maintaining attention and anxiety, according to the NIH.

The disorder is the result of a single missing enzyme – SSADH – because of a mutation in the gene that produces the enzyme.  The enzyme is involved in breaking down a neurotransmitter – GABA – whose primary role is to balance the electrical activity in the brain by selectively inhibiting neurotransmission, according to the NIH.

The absence of the enzyme results in an increase in GABA and a related molecule known as GHB, particularly in the central nervous system, but it is not clear how an increase in the two causes the symptoms of the disorder.  Those processes are a key focus of research in the Gibson laboratory at WSU.  Of interest, GHB gained headlines in the late ‘90s as an illicitly consumed drug of abuse.

There are only approximately 500 cases of SSADH deficiency worldwide, but the long-term significance of the research is its identification of effective treatment for this disorder and other similar inherited disorders that disturb GABA, Gibson said.
Gibson has spent his career studying a specific group of inherited disorders of metabolism. Metabolism is the set of enzyme-catalyzed biochemical transformations that sustain living organisms.  Gibson studies a group referred to   as Mendelian disorders, which have a specific pattern of inheritance and are caused by a single gene abnormality in the DNA, resulting in a single enzyme defect responsible for the disorder.

Gibson’s collaborators and co-PIs on this project are Dr. William H. Theodore of the Clinical Epilepsy Section of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, and Drs. Phillip L. Pearl and Robert J. McCarter, Jr.,  of the Children’s National Medical Center in Washington, D.C.

In their clinical trial of the amino acid taurine in SSADH-deficient patients, the researchers have attempted to block the brain transport of GABA and thereby decrease its high levels in the patients.  In pilot studies, preliminary findings suggest there may be some improvements in behavioral parameters, but only eight of eighteen targeted enrollees have completed the trial, and the final results are pending.   Studies with taurine are a component of an ongoing, separate NIH grant that has just recently transferred with Gibson to the WSU College of Pharmacy.

Gibson was most recently chair of the Biological Sciences Department at Michigan Technological University in Houghton, Mich. He also is a past professor at the University of Pittsburgh School of Medicine and the Oregon Health & Science University in Portland.

More about the experimental drug SGS742 can be found here.