Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare inborn error of the GABA degradative pathway described in approximately 300 patients. The enzyme defect results in accumulation of 4-hydroxybutyric acid (GHB), a compound with unusual neuropharamacologic properties. Clinically, the phenotype is non-specific, featuring psychomotor retardation, hypotonia and speech delay. Currently, there is no effective treatment, and little is known about pathomechanisms or neuropathophysiology. To overcome these gaps in our knowledge, we will develop a murine model of SSADH deficiency and address the following Aims and questions: 1) what are the pathologic findings in the murine model and how do they correlate with the human disease? 2) what role does GHB play in the development of disease pathology?; and 3) can the murine model provide a useful vehicle for development of new preclinical treatment paradigms (encompassing pharmacologic, hematopoietic replacement and hepatocyte repopulation approaches).
These Aims address our long-term objective of developing effective treatment strategies for patients with SSADH deficiency. The research design encompasses development of the knockout followed by characterization of the biochemical/behavioral phenotype and therapeutic approaches at Oregon Health Sciences University with neurologic characterization at the Hospital for Sick Children in Toronto. This design brings considerable expertise to the proposal, employing biochemical, morphologic, enzymatic, molecular, histologic, behavioral, neurochemical and transplantation approaches. Our hypothesis is that GHB has a major role in disease pathology, because it is known that GHB interacts with many neurotransmitter receptors and signaling pathways. Many compounds which act in these systems, and which may have therapeutic value in SSADH-deficient patients are commercially available. Thus, the use of these drugs in a murine model of SSADH deficiency will provide insight into the pathophysiology of the disorder as well as potential new therapeutic strategies.
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