N-CARBAMYLGLUTAMATE (CARBAGLU) IN THE TREATMENT OF HYPERAMMONEMIA

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hyperammonemia associated with several rare inherited disorders frequently causes mental retardation, developmental disabilities and death. The overall goal of this study is to investigate the short-term efficacy and safety of the orphan drug, N-Carbamyl-L-glutamate (Carbaglu , abbreviated as NCLG), for the treatment of hyperammonemia in rare inherited disorders: carbamyl phosphate synthetase I (CPSI) deficiency, NAGS deficiency, propionic acidemia (PA) and methylmalonic acidemia (MMA). The primary aims are: 1. To investigate whether 3-day treatment with NCLG can improve or restore ureagenesis capacity in patients with CPSI deficiency using as surrogate markers: [13C] label incorporation into urea and plasma levels of ammonia, urea and glutamine. 2. To investigate whether ureagenesis capacity is deficient in patients with PA and MMA using [13C] incorporation into urea and whether 3-day treatment with NCLG can improve or restore ureagenesis capacity in all or some of these patients. 3. To evaluate the safety of short-term (3-day) treatment with NCLG in the above patients using clinical and laboratory parameters. The hypothesis is that ureagenesis capacity as evidenced by [13C] incorporation into urea is deficient in each of these four disorders and that treatment with NCLG will improve or restore ureagenesis in patients affected by them. The study will be conducted in the General Clinical Research Centers (GCRC) of the Children's National Medical Center, Washington, D.C. and the Children's Hospital of Philadelphia. Patients (1 day to 70 years of age) with any of the four disorders are eligible for the study. They will all be tested in a short-term trial using surrogate markers (incorporation of [13C] label from Na-acetate into urea, and plasma levels of ammonia, urea and glutamine) before and immediately following 3 days of treatment with NCLG. The patients will also be evaluated for short-term safety of NCLG using clinical and laboratory parameters. The results of this study will provide important efficacy data, which should help to bring Carbaglu ) to the US market for the benefit of patients with any of these orphan diseases found to be responsive to NCLG in this trial.