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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK036729-24S2
Application #
8033363
Study Section
Special Emphasis Panel (ZRG1-GTIE-A (01))
Program Officer
Mckeon, Catherine T
Project Start
2010-04-01
Project End
2011-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
24
Fiscal Year
2010
Total Cost
$101,500
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Pandey, Manoj Kumar; Jabre, Nicholas A; Xu, You-Hai et al. (2014) Gaucher disease: chemotactic factors and immunological cell invasion in a mouse model. Mol Genet Metab 111:163-71
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