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Identification of effective drug targets in treating Glutaric aciduria type 1 disease

Ediga, Raga Deepthi

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Abstract

Glutaric aciduria type I (GA‐I) is an autosomal recessive cerebral organic aciduria,caused by a defective GCDH enzyme. This protein lies in the common final catabolic pathway of L‐lysine, L‐hydroxy lysine and L‐tryptophan. Individuals possessing GCDH enzyme deficiency are biochemically characterized by the accumulation of neurotoxic metabolites glutaryl‐CoA, GA, 3‐OH‐GA as well as non‐toxic C5DC in their tissues and body fluids. If untreated, most of the individuals develop an acute encephalopathic crisis causing striatal damage during a finite period of brain growth, resulting in complex movement disorder with predominant dystonia, most commonly between 3 months to 3 years of age. Individuals, diagnosed before the onset of irreversible neurologic symptoms can be prevented from striatal damage, if they are treated with a special diet consisting of low L‐lysine content,supplementation with carnitine and essential amino acids as well as emergency treatment on demand. Even though the currently followed metabolic treatment is predicted to be safe and effective, a significant number of patients still suffer from striatal damage despite early diagnosis and treatment. In addition, recent findings report on extra‐striatal, extra cerebral and non‐neurologic abnormalities despite the current regimen followed. This highlights the prerequisite for the discovery of novel,safe and more efficient long‐term treatment strategies. In this thesis, we hypothesize that pharmacological inhibition of upstream enzymatic steps of the lysine degradation pathway, prior to GCDH, will prevent toxic metabolite accumulation and, consequently, induction of clinical disease phenotype in Glutaric aciduria Type I. To this end, Dehydrogenase E1 and transketolase domain containing 1 (DHTKD1)(approach1) and Aminoadipate amino transferase (AADAT) (alternate approach 2) are targeted and our hypothesis is tested in genetically modified cell models,Glutaric aciduria type I patient cell lines, and knockout mouse models. We therefore,developed a Dhtkd1‐/‐/ Gcdh‐/‐ mouse model and studied its characteristics biochemically and clinically after giving high lysine (4.7% (w/w) or 235mg of Llysine in food) in diet. Our studies showed that DHTKD1 knockout was unable to rescue GA‐I phenotype in Dhtkd1+/+/ Gcdh‐/‐ mice as seen by the accumulated GA levels on GCMS measurement. Since our in vivo data strongly suggested that DHTDK1 is not a suitable drug target in GA‐I, we did not proceed with drug testing.Next, we evaluated the commercially available, patented AADAT inhibitor PF04859989 in GCDH‐deficient cells. Indeed, the inhibitor treatment significantly reduced GA accumulation in these cells. Overall this thesis suggests that,pharmacological inhibition of AADAT is a novel therapeutic strategy for GA‐I.

Item Type: Dissertation
Supervisor: Freichel, Prof. Dr. Marc
Date of thesis defense: 15 November 2018
Date Deposited: 11 Dec 2018 14:34
Date: 2018
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
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