Regeneration of Epidermal Nerves in Human Diabetic Neuropathy

人类糖尿病神经病变中表皮神经的再生

基本信息

批准号：
10161766
负责人：
Angela Hansen
金额：
$ 98.55万
依托单位：
WINSANTOR, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10161766
关键词：
Achievement Address Aftercare American Amputation Animal Model Area Assessment tool Australia Biopsy Blood - brain barrier anatomy Chronic Clinical Data Clinical Research Clinical Trials Data Detection Diabetes Mellitus Diabetic Neuropathies Distant Dose Evaluation Excision FDA approved Fiber Formulation Funding Future Growth HIV HIV Infections Human Impairment In Vitro Location Measures Mediating Metabolic Metabolism Mitochondria Muscarinic Acetylcholine Receptor Muscarinic Antagonists Muscarinic M1 Receptor National Institute of Diabetes and Digestive and Kidney Diseases Natural regeneration Nerve Nerve Fibers Nervous System Physiology Neurologic Neurons Neuropathy Non-Insulin-Dependent Diabetes Mellitus Pain Patients Peripheral Peripheral Nerves Peripheral Nervous System Diseases Pharmaceutical Preparations Pharmacology Phase Phase I Clinical Trials Pirenzepine Positioning Attribute Prediabetes syndrome Protocols documentation Publishing Quality of life Reporting Research Design Rodent Model Safety Secondary to Sensory Sensory Nerve Endings Site Skin Skin Tissue Small Business Innovation Research Grant Therapeutic Time Topical application Translating Type 2 diabetic United States National Institutes of Health Urinary Incontinence Visit base body system chemotherapy cholinergic clinical development cohort commercialization cost cost efficient density design diabetic patient drug efficacy effective therapy glycemic control hydrophilicity improved in vivo indexing nerve supply novel oxybutynin pain relief pain score phase 2 designs phase 2 study phase III trial preclinical study prevent primary endpoint secondary endpoint side effect success tool treatment duration treatment site

项目摘要

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.

项目摘要/摘要没有FDA批准的疗法来预防或逆转周围神经病，这种情况会困扰美国约有3000万人，通常与糖尿病，化学疗法或HIV感染有关。我们发表的临床前研究表明，周围神经代谢和生长是重新培训在体外和体内条件下，通过胆碱能抑制线粒体活性通过神经元M1受体。去除毒蕈碱拮抗剂的胆碱能“制动”促进了神经在多种糖尿病，化学疗法和HIV-的动物模型中，生长并预防神经病诱导神经病。通过R21资金获得的概念临床数据证明了局部毒蕈碱受体拮抗剂的治疗可以显着逆转表皮内神经的丧失糖尿病神经病患者皮肤的纤维（IENF），并改善神经系统的多个指数生活和生活质量。该探索性数据鼓励当前的SBIR阶段IIB应用程序。在第一年，我们将通过确定局部持续时间的最短持续时间在我们的初步临床研究基础上进行可以在受试者皮肤中产生统计学上显着增加神经密度的治疗 2型糖尿病和神经病。此信息对于潜水员临床的未来设计将很重要试图评估针对小纤维神经病的药物效率的研究，并将指导我们的设计第二阶段研究。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，局部毒蕈碱受体拮抗剂，也建立效率是否仅限于局部应用站点还是系统地扩展。主要端两项研究的点将是治疗部位的皮肤密度。次要终点将包括位点的多个神经系统评估工具评分，生活质量评分，疼痛评分和IENF密度远离药物施用。我们预计这些研究的成功完成将定位 Winsantor Inc.将局部毒蕈碱拮抗剂公式推向FDA批准作为第一个治疗糖尿病神经病。