Novel insights into treatment strategies for hyperammonemia-associated urea cycle disorders and organic acidurias.

Investigador: Margarida F.B. e Silva
Ph.D., Aux Prof FFUL; Metabolism and Genetics Group at iMed.UL

Hyperammonemia in paediatric patients is mostly related to inborn errors of metabolism (IEM) including urea cycle disorders and certain organic acidurias. The rise of toxic ammonia levels may have devastating consequences on neurodegeneration and neurodevelopment. Preventive strategies of metabolic deterioration and more effective therapeutic options are definitely needed. Few studies have assessed the efficacy of novel therapies, especially tailored to the various phenotypes and IEM. This research proposal puts forward the hypotheses that: 1) hyperammonemia is linked to changes in cofactors or redox status affecting energy metabolism and resulting in mitochondrial dysfunction; 2) drug design profits of associated small molecules to improve their efficacy, reducing levels of toxic ammonia and surpassing the metabolic imbalances associated with the genetic underlying cause of IMD.

Abstract

To this end, combinatorial strategies of known nitrogen-scavenging agents, cofactors or substrates will be investigated in vitro using a human hepatoma cell model or using animal models of HA. Bioassays using targeted mass spectrometry-based techniques will be optimized for patient-derived fluids, cultured cells or exometabolome. Through the use of stable-isotope labelled standards, bioanalytical approaches will be devised and validated to trace metabolism and to evaluate enzyme activity. The metabolic modulation of target pathways affecting ammonia metabolism will be investigated using small molecules and precursors to evaluate activation/inhibitory effects. The proposed study will provide novel insights into the molecular mechanisms of ammonia pathogenesis linked to the major pathways of energy dysregulation focused on proximal or distal reactions of urea cycle, krebs cycle and fatty acid oxidation. Expected results will lead to a deeper understanding of pharmacodynamics of tested strategies, predicted to ameliorate mitochondrial function and ammonia detoxification.