Regeneration of Epidermal Nerves in Human Diabetic Neuropathy

项目摘要/摘要 没有FDA批准的治疗方法来预防或逆转周围神经病变，这是一种折磨人的疾病 在美国大约有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，周围神经的新陈代谢和生长是重新训练的。 在体外和体内条件下胆碱能抑制线粒体活性通过 神经元型M1受体。M受体拮抗剂去除胆碱能“刹车”可促进神经功能 在糖尿病、化疗和艾滋病毒的多种动物模型中生长和预防神经病变- 诱导性神经病变。通过R21基金获得的概念验证临床数据表明，局部用药 用M受体拮抗剂治疗可以显著逆转表皮内神经的丢失 糖尿病神经病变患者皮肤中的纤维(IENF)与改善神经功能多项指标 功能和生活质量。这一探索性数据鼓励了目前SBIR第二阶段B的应用。在……里面 第1年我们将在我们的初步临床研究的基础上，确定局部用药的最短持续时间 治疗可以在统计学上显着增加患者皮肤中的神经密度 2型糖尿病和神经病变。这些信息将对未来不同临床设计具有重要意义。 寻求评估药物对小纤维神经病疗效的研究，并将指导我们的设计 第二阶段研究。在第二年到第三年，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使用局部毒鼠强受体拮抗剂，并建立 疗效是否仅限于局部用药部位或全身推广。主端 这两项研究的重点都是治疗部位的皮肤IENF密度。次要端点将包括 多项神经评估工具评分、生活质量评分、疼痛评分和IENF密度 远离药物申请。我们预计，这些研究的成功完成将使 WinSanTor Inc.将把一种局部使用的毒副作用拮抗剂配方推向FDA批准，成为第一个 糖尿病神经病变的治疗。

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.