The principal investigator would apply his expertise in molecular biology to the emerging field of molecular medicine. He will focus on a devastating pediatric neurological syndrome arising from a inborn error of pyruvate metabolism. The long term goal of the candidate is to develop clinical protocols for somatic gene therapy. This award will make it possible for the candidate to receive training in pediatric neurology, neuropathology, neuroradiology and medicine; and to apply this training in ongoing clinical research. It will also provide a period in which the candidate will further develop teaching skills in the context of the Pediatric Neurology Resident Training Program. The Colleen Giblin Laboratories at Columbia-Presbyterian Medical Center under the direction of Dr. Darryl C. De Vivo, the mentor for the proposal, contains an extensive repository of sin fibroblast cultures from which to draw patient material for this study. The Division for Pediatric Neurology is renowned for the quality of its post-graduate training program. The candidate would thus be exposed to ongoing clinical activities in pediatric neurology, and would further benefit from the manifold research activities at the Health Sciences Campus of Columbia University. The biotin-containing enzyme pyruvate carboxylase (PC) [ECC 6.4.1.1] catalyzes the synthesis of oxaloacetate in a major anaplerotic reaction, and also has a major metabolic role in gluconeogenesis. Primary forms of PC deficiency are characterized by metabolic crises of lactic acidosis, hypotonia, encephalopathy and are refractory to current therapies. Initially, the types of mutations leading to loss of enzyme function in patients will be characterized. Subsequently, improved diagnostic methods, and a better understanding of the molecular pathology will be developed using a variety of molecular biological, biophysical and immunological methods. Tissue culture systems for investigation of defects in pyruvate metabolism, and for their correction with appropriate gene therapy vectors will be achieved in years two through four. The fifth and final year will be spent in preparation for human gene therapy trials and in pursuing renewable funding for this work.
