Substrate reduction as a novel therapeutic strategy for Glutaric Aciduria Type 1

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Project Summary / Abstract In this project, the investigators propose to develop a novel treatment option for glutaric aciduria type 1 (GA1; MIM 231670). GA1 is an autosomal recessive inborn error of lysine, hydroxylysine and tryptophan degradation. Patients can present with macrocephaly and may develop a complex movement disorder due to striatal injury after an acute encephalopathic crisis. The disorder is caused by a deficiency of glutaryl-CoA dehydrogenase (GCDH), which leads to the accumulation of neurotoxic glutaric acid and 3-hydroxyglutaric acid. GA1 is considered a treatable disorder and therefore included in newborn screening programs in many countries. However, current treatment consists of dietary intervention, carnitine supplementation, and emergency care. This treatment paradigm requires intense efforts from both caregiver and patient. It must be meticulously maintained, but in some patients neurological disease may still develop. These limitations demonstrate the need for novel therapeutic options with improved efficacy and convenience. The investigators hypothesize that by using inhibitors upstream in the lysine degradation pathway, accumulation of neurotoxic glutaric acid and 3-hydroxyglutaric acid in GA1 can be diverted into more tolerable metabolites. It has been shown that hyperlysinemia is a biochemical phenotype without clinical significance. It is caused by mutations in AASS encoding 2-aminoadipic semialdehyde synthase (AASS), which is an enzyme upstream of GCDH in the lysine degradation pathway. The investigators obtained preliminary data showing that deletion of AASS/Aass limits metabolite accumulation in cell and mouse models for GA1. This suggests that AASS is a suitable and potentially safe target for treatment of GA1. Thus, the overall objective of this proposal is to identify novel small-molecule inhibitors of the lysine-oxoglutarate reductase (LOR) domain of AASS suitable for future medicinal chemistry optimization. In AIM 1, the investigators will identify enzyme inhibitor candidates through both a small molecule high-throughput screen (HTS) and computational (virtual) screening using their recently obtained 2.2Å LOR crystal structure. Then, using structure-based drug design, medicinal chemistry methods and co-crystallization, they will develop preliminary structure-activity relationships to validate new hit analogs as drug-like scaffolds. All active hits from the HTS and virtual screening will be further evaluated in AIM 2 in order to generate a prioritized list of commercial compounds with good medicinal chemistry properties. In AIM 3 selected validated hit molecules will be tested in vitro in cell-based models of GA1 by monitoring established biomarkers for the inhibition of LOR and the disease. Combined, these three aims will yield not only highly validated hit inhibitors of LOR that can be further developed for treatment of GA1, but also important additional data on the biochemistry and physiology of lysine degradation.