Novel Approaches to Mend Deficient Glycosylation

Burnham Institute For Medical Research, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): 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.