Our overall goal is to determine the short-term efficacy of N-carbamyl-L-glutamate (NCG) for the treatment of five inborn errors of metabolism that cause hyperammonemia and consequent brain damage: N-acetylglutamate synthase (NAGS) deficiency, carbamyl phosphate synthetase I (CPSI) deficiency, propionic acidemia (PA), methylmalonic acidemia (MMA) and hyperinsulinism and hyperammonemia syndrome (HHS).
Our specific aims are: 1. To determine whether a 3-day treatment with NCG improves or restores ureagenesis in patients with NAGS deficiency, CPSI deficiency, PA, MMA and HHS as evidenced by 13C incorporation into urea, concentrations of plasma ammonia, urea and amino acids and brain glutamine concentrations measured by magnetic resonance spectroscopy. The results in patients with each of the five inherited disorders will be compared to those obtained in healthy adult volunteers (normal controls). In addition, the results of patients with NAGS deficiency, who we expect to respond best to NCG (positive controls), will be compared to the results from the other four disorders to gauge their degree of correction of ureagenesis in response to NCG. 2. To evaluate the safety of short-term (3-day) treatment with NCG in the healthy volunteers and patients. Clinical and laboratory safety parameters will be evaluated in all participants, including idiosyncratic symptoms and changes in blood counts and liver and kidney functions. Our hypothesis is that NCG will ameliorate deficient ureagenesis in these congenital disorders. This proposal will provide important efficacy data for a novel treatment of several rare congenital 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 of diverse etiology and treatment with valproic acid. Carbaglu grant narrative Elevated ammonia levels in the blood can cause brain damage, developmental disabilities and it can be fatal. N-acetylglutamate (NAG) is a small molecule in the liver that is essential for the urea cycle, keeping blood ammonia levels below levels that are toxic to the brain. We have reason to believe that N-carbamylglutamate (Carbaglu), a chemical that is very similar to NAG, but that unlike NAG is not broken down in the body, can mimic the effect of NAG to decrease ammonia levels in patients with a number of inherited metabolic diseases. This project will investigate whether Carbaglu can improve the urea cycle in patients with 5 different genetic diseases associated with high ammonia levels. If the results confirm our hypothesis, these patients can be treated with Carbaglu to keep their ammonia level at normal or close to normal levels, protecting them from brain damage.
Showing the most recent 10 out of 13 publications
