Regeneration of Epidermal Nerves in Human Diabetic Neuropathy

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Project Summary/Abstract There is no FDA-approved therapy to prevent or reverse peripheral neuropathy, a condition that afflicts around 30 million people in the US and is often associated with diabetes, chemotherapy or HIV infection. Our published preclinical studies have revealed that peripheral nerve metabolism and growth is retrained under both in vitro and in vivo conditions by cholinergic suppression of mitochondrial activity acting via neuronal M1 receptors. Removal of this cholinergic “brake” by muscarinic antagonists promotes nerve growth and protects against neuropathy in multiple animal models of diabetes, chemotherapy and HIV- induced neuropathy. Proof of concept clinical data obtained via R21 funding demonstrates that topical treatment with a muscarinic receptor antagonist can significantly reverse loss of intra-epidermal nerve fibers (IENF) in the skin of patients with diabetic neuropathy and improve multiple indices of neurological function and quality of life. This exploratory data encourages the present SBIR Phase IIB application. In Year 1 we will build on our preliminary clinical study by determining the shortest duration of topical treatment that can produce a statistically significant increase in nerve density in the skin of subjects with type 2 diabetes and neuropathy. This information will be important for the future design of diverse clinical studies that seek to assess drug efficacy against small fiber neuropathy and will guide design of our Phase II studies. In Year 2-3, we will perform a clinical trial to determine the most effective dose of a topical muscarinic receptor antagonist over the time frame identified in Year 1 and also to establish whether efficacy is restricted to the site of topical application or extends systemically. The primary end point for both studies will be skin IENF density at the treatment site. Secondary end points will include multiple neurological assessment tool scores, quality of life scores, pain scores and IENF density at sites distant from drug application. We anticipate that successful completion of these studies will position WinSanTor Inc. to advance a topical muscarinic antagonist formulation towards FDA approval as the first treatment for diabetic neuropathy.