RESEARCH &RELATED Other Project Information 6. Project Summary/Abstract: The proposed research focuses on the in vivo evaluation of pharmacological chaperone therapies in our mouse models of Gaucher disease, a common and prototype inborn error of metabolism. The proposed studies address the hypotheses that: 1) Prototype competitive inhibitors, termed pharmacologic chaperones, can increase selected mutant enzymes' activity/function and be therapeutic in vivo. This has import for the visceral variants, but also, and importantly, for the CNS variants since current enzyme (ET) or gene therapies are not available for these common variants of Gaucher disease. 2) Such chaperones could be used to enhance the efficiency of ET or gene therapy by improving the therapeutic enzyme's activity and/or delivery. The insufficient activity of acid ?-glucosidase [GCase] initiates the pathological processes, and normalization of substrate glucosylceramide [GC] flux in tissues is essential to stop disease progression and to restore health. The objectives of this proposal are to evaluate the in vivo effects of selected pharmacologic chaperones on tissue specific, glycosphingolipid (GSL) storage and responses using our unique mouse models with knock-in GCase point substitutions as test systems. Selected ?knocked-in?mutations in GCases exhibit correctible deficits in catalytic activity, of disrupted lysosomal trafficking, and/or of stability properties ex vivo in cells. Correlations will be made between the ex vivo and in vivo effects on the properties of the mutant enzymes since the ex vivo (dividing cells in culture) and in vivo (mostly non-dividing tissue cells) mechanisms or effects may differ. Efforts will be directed to defining the levels of GCase activity in tissues needed to correct cellular GC metabolism. GCase deficient mutant mouse studies will be used to evaluate the in vivo capacity of selected chaperones to reverse/improve histological and lipid abnormalities. These studies are grounded in the availability of our gba point mutated mouse models, systems for GCase characterization, our mice with in vivo controllable, tissue specific, expression of GCase, and our preliminary data strongly supporting in vivo therapeutic effects of selected pharmacological chaperones. RESEARCH &RELATED Other Project Information 7. Project Narrative: Gaucher disease is a lysosomal storage disorder that has the potential to be screened for in the newborn period. The disease is multisystemic and can involve visceral organs and the brain. The current enzyme therapy is expensive and inconvenient, and the effects are partial. Thus, there is a need to develop new therapies. Based on molecular engineering, specific compounds, termed chaperones, will be used to enhance the activity of the Gaucher disease enzyme, GCase, in specifically developed mouse models of the human disease. This approach offers the potential for more complete therapy, including the CNS, as well as less expensive and more convenient therapy for this disease as prototype for this class of disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-GTIE-A (01))
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Mckeon, Catherine T
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Cincinnati Children's Hospital Medical Center
United States
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