SUMMARY Congenital Disorders of Glycosylation (CDG) is a group of over 150 diseases characterized by limited ability to attach glycans to proteins and lipids. The most common form, loss of phosphomannose mutatase-2 activity (PMM2-CDG), is an orphan disease affecting approximately 1500 patients worldwide. CDG typically presents as severe disease in the first few years of life and is lethal in 20% of infantile cases. Children with PMM2-CDG have a range of symptoms, including hypotonia, ataxia, neuropathy, severely delayed language and motor development, inability to walk, and IQ of 40 to 70. Adult patients display mild to severe physical and mental disabilities. Current treatment for CDG consists only of palliative care. No therapeutic is approved for use. Replacement therapies with monosaccharides, such as mannose-1-phosphate, galactose, fucose, as well as other dietary supplements, have shown little efficacy in PMM2-CDG. Severity of disease is correlated with degree of enzyme loss: <7% enzyme activity is lethal, whereas >50% activity yields no symptoms. Maggie’s Pearl has discovered several compounds that increase the activity of the mutant PMM2 enzyme in several models of PMM2-CDG, including fibroblasts derived from PMM2 patients. Many of these compounds are aldose reductase inhibitors (ARIs), and one of them, Epalrestat, appears to be a safe drug candidate. It has been used for over 27 years in Japan for treatment of diabetic neuropathy in adults. However, the drug is not approved for any indication in the US. Maggie’s Pearl has tested Epalrestat in a single-patient trial. The young patient showed positive results after just 4 months of treatment, with no adverse effects after 18 months of Epalrestat. The proposed SBIR will expand this study to a double blind, single-crossover trial of 30 childhood PMM2-CDG patients over the course of three years. Similar success of Epalrestat in this trial would offer life-changing improvements for patients worldwide.

NARRATIVE Congenital Disorders of Glycosylation (CDG) affects several thousand patients worldwide. Maggie’s Pearl has discovered several compounds, including the known drug Epalrestat, that appear to relieve the cause of the disease. The proposed SBIR study will fund a 30-patient, double blind, single-crossover trial to confirm the safety and efficacy of Epalrestat in one form of CDG.