Congenital disorders of Glycosylation (CDG) are autosomal recessive diseases that impair the synthesis of N-linked oligosaccharides. The most common form, CDG-la, results from insufficient phosphomannomutase (PMM2) needed to convert Mannose-6-P to Mannose-1-P, the precursor for GDP-Mannose. No therapy is available for this multisystemic disorder, which is characterized by mental and psychomotor retardation, seizures, hypotonia, failure to thrive, and coagulopathy. Although Mannose-1-P does not enter cells, we hypothesize that a membrane permeable form of Man-1-P will enter, replenish the depleted GDP-Man pool, and restore glycosylation. Preliminary results using one such compound are very encouraging. We propose to use normal and glycosylation-deficient human cell lines and a mouse model of CDG to explore the usefulness of such modified compounds as a potential therapy for CDG-la patients. Specifically, we aim to: 1. Synthesize a series of cell-permeable, hydrophobic Man-1-P compounds and test their ability to correct impaired glycosylation in CDG patient-derived cell lines and fibroblasts from glycosylation-deficient mice. 2. Determine the clearance, fate, distribution, turnover, and utilization of the lead compounds in normal mice. 3. Use the lead compound(s) to correct impaired glycosylation in a mouse model of CDG as assessed by coagulopathy and protein losing enteropathy. The information derived from these studies may be useful for design and analysis of cell-permeable derivatives of GDP-Mannose or N-acetylmannosamine-6-P to treat other types of glycosylation disorders such as other types of CDG and inclusion body myopathy, respectively.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK065091-01
Application #
6676717
Study Section
Special Emphasis Panel (ZRG1-PBC (04))
Program Officer
Mckeon, Catherine T
Project Start
2003-08-01
Project End
2006-05-31
Budget Start
2003-08-01
Budget End
2004-05-31
Support Year
1
Fiscal Year
2003
Total Cost
$372,480
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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