Dissertation/Thesis Abstract

Novel therapeutics and pathomechanisms in human mendelian disorders: Phenylketonuria, maple syrup urine disease, and succinic semialdehyde dehydrogenase deficiency
by Vogel, Kara Rain, Ph.D., Washington State University, 2014, 240; 3640086
Abstract (Summary)

The body of this dissertation is focused on understanding the pathomechanisms and paving the way for new treatment paradigms in human metabolic disease, particularly phenylketonuria (PKU), maple syrup urine disease (MSUD), and succinic semialdehyde dehydrogenase (SSADH) deficiency.

Phenylketonuria and MSUD are heritable aminoacidopathies displaying aberrant cerebral transport of large neutral aminoacids. This work presents evidence that non-physiological amino acids (NPAAs) have pharmacodynamic efficacy in selective exclusion of phenylalanine from the brain of phenylketonuric mice. Data is presented for feeding and intraperitoneal injection studies of various NPAA's including methyl-aminoisobutyric acid (MAIB), and some selected MAIB-related alkanoic acid analogues. My data indicates that MAIB is the most selective phenylalanine transport inhibitor identified thus far. Regional brain amino acid studies in intermediate MSUD mice fed low (6%) and high (19%) protein chow suggest that despite varying improvements in the pathophysiological branched-chain amino acids (leucine, isoleucine and valine) in serum, glutamine, aspartate, glutamate, gamma-aminobutyric acid (GABA), asparagine, citrulline, and serine levels remained unchanged in the brain, demonstrating that dietary correction of MSUD monitored in blood does not accurately reveal corrections in brain biochemistry, providing important insights for human patients. Moreover, I have documented similar findings in PKU mice.

The final chapters of this work contain a review of the treatment prospects for SSADH disorder (a defect in GABA metabolism), and our collaborative work with the University of California focused on hyperphysiological GABA's on mTOR-driven selective autophagy. SSADH-deficient mouse studies utilizing electron microscopy to quantify mitochondria in liver and brain tissues suggest mitophagic inhibition may play a causal role in the findings of oxidative stress in patients and mice. The impact of these findings are discussed from a pharmacological viewpoint including the scope of treatment of hyperGABAergic disorders.

Lastly, I have included my literature characterization of hepatocyte transplantation (HTx) for inborn errors of metabolism which suggests that we can attempt therapeutic HTx in a murine model of a new disease, transaldolase deficiency, with a goal of gaining almost complete hepatic repopulation with gene-replete (wild-type) cells. My final article is a preclude to future postdoctoral work in the area of liver repopulation and novel therapeutic approaches.

Indexing (document details)
Advisor: Gibson, K. Michael
Commitee: Marsh, Susan, Potter, Nancy, Wisor, Jonathan
School: Washington State University
Department: Pharmaceutical Sciences
School Location: United States -- Washington
Source: DAI-B 76/02(E), Dissertation Abstracts International
Subjects: Molecular biology, Pharmacy sciences
Keywords: Hepatocyte transplant, Inherited disorders, Maple syrup urine disease, Metabolic disease, Phenylketonuria, Succinic semialdehyde dehydrogenase disorder
Publication Number: 3640086
ISBN: 978-1-321-25241-5
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