Targeting succinyl-CoA:glutarate-CoA transferase as a novel therapeutic strategy for glutaric aciduria type 1 - Project Summary / Abstract In this project, the investigators propose to study and validate the enzyme succinyl-CoA:glutarate-CoA transferase (SUGCT) as a novel pharmacological target for the treatment of glutaric aciduria type 1 (GA1). GA1 is an autosomal recessive inborn error of lysine, hydroxylysine and tryptophan degradation. Patients can present with brain atrophy and macrocephaly, and may develop dystonia after acute encephalopathic crises that lead to striatal degeneration. The disorder is caused by a deficiency of the enzyme glutaryl-CoA dehydrogenase (GCDH), which leads to the accumulation of neurotoxic metabolites such as 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 treatment which requires intense efforts from both caregiver, patient and clinical team. It must be meticulously maintained, but even so neurological disease still develops in 25% of patients, with these negative outcomes reflecting historical health inequities and social determinants of disease. Thus, the treatment needs of GA1 patients are unmet. Development of pharmacological therapies, however, is hampered by limited understanding of pathophysiological mechanisms. The biochemical phenotype of the GA1 mouse model is similar to that of human disease. High lysine exposure of GA1 mice is necessary to induce a clinical phenotype resembling human GA1, but the susceptibility is variable and a significant number of mice remain asymptomatic. Although the genetic background of the mouse model is known to be one of the main modulating factors, the underlying molecular mechanism has previously remained unknown. The investigators have now found that SUGCT, an enzyme directly involved in the metabolism of glutaryl-CoA, is polymorphic between relevant mouse strains, which explains the difference in vulnerability to high lysine exposure. Based on published and preliminary data, the investigators hypothesize that pharmacological SUGCT inhibition is a novel therapeutic option for GA1. The overall objective of this R01 proposal is to further validate SUGCT as a novel therapeutic target for the treatment of GA1 and to develop selective small molecule SUGCT inhibitors to provide pre-clinical proof-of- concept. In order to reach this objective, the investigators propose the following three specific aims. In AIM 1, the investigators will establish the functions of SUGCT through biochemical, cell line and structural biology studies. In AIM 2, the investigators will validate SUGCT as a drug target in GA1 mice through the generation of whole body and tissue-specific Sugct KO mice. In AIM 3, the investigators will identify SUGCT inhibitors through a high-throughput small molecule screen (HTS) and further validate current in-hand hits and new ones through medicinal chemistry. The ultimate goal of this project is to better understand the pathophysiology of GA1 and provide a novel path toward finding pharmacological treatment options for affected patients.
