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.
| Bode, Lars; Salvestrini, Camilla; Park, Pyong Woo et al. (2008) Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function. J Clin Invest 118:229-38 |
| Eklund, Erik A; Freeze, Hudson H (2006) The congenital disorders of glycosylation: a multifaceted group of syndromes. NeuroRx 3:254-63 |
| DeRossi, Charles; Bode, Lars; Eklund, Erik A et al. (2006) Ablation of mouse phosphomannose isomerase (Mpi) causes mannose 6-phosphate accumulation, toxicity, and embryonic lethality. J Biol Chem 281:5916-27 |
| Bode, Lars; Eklund, Erik A; Murch, Simon et al. (2005) Heparan sulfate depletion amplifies TNF-alpha-induced protein leakage in an in vitro model of protein-losing enteropathy. Am J Physiol Gastrointest Liver Physiol 288:G1015-23 |
| Eklund, Erik A; Merbouh, Nabyl; Ichikawa, Mie et al. (2005) Hydrophobic Man-1-P derivatives correct abnormal glycosylation in Type I congenital disorder of glycosylation fibroblasts. Glycobiology 15:1084-93 |
