Regeneration of Epidermal Nerves in Human Diabetic Neuropathy

项目总结/摘要 目前还没有FDA批准的治疗方法来预防或逆转周围神经病变， 在美国约有3000万人，通常与糖尿病，化疗或艾滋病毒感染有关。 我们已发表的临床前研究表明，周围神经代谢和生长受到重新训练， 在体外和体内条件下，通过胆碱能抑制线粒体活性， 神经元M1受体。通过毒蕈碱拮抗剂去除这种胆碱能“制动器”， 在糖尿病、化疗和HIV的多种动物模型中， 诱发性神经病通过R21基金获得的概念验证临床数据表明， 用毒蕈碱受体拮抗剂治疗可显著逆转表皮内神经的丧失 纤维（IENF）在糖尿病神经病变患者的皮肤，并改善神经功能的多个指标 功能和生活质量。该探索性数据鼓励了当前SBIR IIB期应用。在 第1年，我们将在初步临床研究的基础上，确定局部给药的最短持续时间。 治疗，其可以在患有以下疾病的受试者的皮肤中产生神经密度的统计学显著增加： 2型糖尿病和神经病变。这一信息将是重要的未来设计的多样化的临床 这些研究旨在评估药物对小纤维神经病变的疗效，并将指导我们的 II期研究。在第2-3年，我们将进行临床试验，以确定最有效的剂量， 在第1年确定的时间范围内局部使用毒蕈碱受体拮抗剂，并建立 疗效是否局限于局部应用部位或全身扩展。主要终点 两项研究的点将是治疗部位的皮肤IENF密度。次要终点将包括 研究中心的多种神经系统评估工具评分、生活质量评分、疼痛评分和IENF密度 远离药物应用。我们预计，这些研究的成功完成将有助于 WinSanTor Inc.推进局部毒蕈碱拮抗剂制剂向FDA批准，作为第一个 治疗糖尿病神经病变。

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.