N-acetylglutamate (NAG) is an essential cofactorfor carbamyl phosphate synthetase 1 (CPS1), the first and rate limiting enzyme of ureagenesis. This cofactor plays an important role in the regulation of ureagenesis by activating a variable number of CPS1 enzyme molecules. N-carbamyl-L-glutamate (NCG) is a stable functional analog of NAG and can substitute for it in the activation of CPS1. We have shown that this orphan drug (Carbaglu) "cures" the hyperammonemia caused by N-acetylglutamate synthase (NAGS) deficiency and can ameliorate the hyperammonemia in disorders with secondary deficiency of NAGS (propionic acidemia). We have also demonstrated that NCG increases the rate of ureagenesis in healthy individuals. Our overall goal in this project is to determine the short-term and long term efficacy of NCG in the treatment of two urea cycle disorders that cause hyperammonemia and consequent brain damage: CPS1 deficiency and OTC deficiency.
Our specific aims are: 1. To determine whether short-term (3 day) treatment with NCG will improve otherwise compromised ureagenesis in patients with CPS1 or OTC deficiency. In addition, to determine whether treatment with NCG in OTC deficiency increases the production of nitrogen containing intermediates, orotic acid and orotidine as a mechanism for eliminating nitrogen in lieu of urea. 2. To evaluate whether long-term (6 month) treatment with NCG will maintain the putative biochemical improvements achieved after short-term therapy and whether these improvements correlate with better clinical outcome. The underlying hypothesis is that NCG will access liver mitochondria and augment CPS1 activity by stimulating this enzyme. Consequently, more ammonia will be incorporated into carbamyl phosphate and/or urea and/or pyrimidines, thus enhancing waste nitrogen elimination. We will employ screening with surrogate stable isotopes and other biochemical and neuroimaging markers to screen for NCG (Carbaglu) effect on nitrogen metabolism during a short-term (3 day) trial. Those patients who respond by augmenting nitrogen disposal in response to NCG will be offered enrollment into a long term (6 month)

Public Health Relevance

This proposal will provide important efficacy data for a novel treatment of rare urea cycle disorders that are associated with hyperammonemia that often is refractory. Successful conclusion of the study also may afford a rationale for the investigation of other diseases and conditions that are complicated by hyperammonemia, including liver failure and treatment with valproic acid.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Children's Research Institute
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