Orphan drugs in development for urea cycle disorders: current perspectives

Johannes Häberle,1 Shawn E McCandless2 1Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland; 2Center for Human Genetics, University Hospitals Case Medical Center, and Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA Abstract: The urea cycle disorders are caused by deficiency of one of the six hepatic enzymes or two transporters involved in detoxification of ammonia. The resulting hyperammonemia causes severe brain injury unless aggressive steps are taken to reduce the accumulation of ammonia, which is thought to be the most toxic metabolite. This review describes the current state of chronic management of urea cycle disorders, focusing on new and emerging therapies. Management strategies include the mainstay of treatment, namely dietary protein restriction and supplementation with l-arginine or l-citrulline. Several currently approved medications utilize and enhance alternative pathways of waste nitrogen excretion (sodium benzoate, sodium phenylacetate, sodium phenylbutyrate in several formulations, and glycerol phenylbutyrate), working through conjugation of the drug to either glycine (in the case of benzoate) or glutamine, the products of which are excreted in the urine. Carglumic acid activates the first committed step of conversion of ammonia to urea, carbamoylphosphate synthetase, and thus effectively treats defective synthesis of the endogenous activator, N-acetylglutamate, whether due to genetic defects or biochemical inhibition of the N-acetylglutamate synthase enzyme. Approaches to neuroprotection during episodes of hyperammonemia are discussed, including the use of controlled hypothermia (brain cooling), as well as proposed, but as yet untested, pharmacologic therapies. Finally, cell-based therapies, including liver transplantation, infusion of fresh or cryopreserved hepatocytes, use of stem cells, and new approaches to gene therapy, are reviewed. Keywords: urea cycle disorders, inherited hyperammonemias, orphan drugs, phenylbutyrate, N-carbamyl-l-glutamate