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：
9922282
负责人：
Angela Hansen
金额：
$ 99.56万
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 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9922282
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.

项目概要/摘要目前尚无 FDA 批准的治疗方法可以预防或逆转周围神经病变（一种困扰周围神经病变的疾病）在美国大约有 3000 万人，并且通常与糖尿病、化疗或 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得到了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毒蕈碱拮抗剂消除神经元 M1 受体可促进神经功能。在糖尿病、化疗和艾滋病毒的多种动物模型中促进生长并防止神经病变通过 R21 资助获得的概念验证临床数据表明，局部治疗用毒蕈碱受体拮抗剂治疗可以显着逆转表皮内神经的损失糖尿病神经病变患者皮肤纤维（IENF），改善神经系统多项指标该探索性数据鼓励目前 SBIR IIB 期的应用。第一年，我们将在初步临床研究的基础上确定局部用药的最短持续时间可以使受试者皮肤神经密度产生统计上显着增加的治疗该信息对于未来不同临床的设计非常重要。旨在评估针对小纤维神经病的药物疗效的研究，并将指导我们的设计在第 2-3 年，我们将进行临床试验以确定最有效的剂量。在第一年确定的时间范围内局部使用毒蕈碱受体拮抗剂，并建立功效是否仅限于局部应用部位或扩展到全身。两项研究的重点都是治疗部位的皮肤 IENF 密度，次要终点包括。多种神经评估工具评分、生活质量评分、疼痛评分和现场 IENF 密度我们预计这些研究的成功完成将远离药物应用。 WinSanTor Inc. 将推进一种外用毒蕈碱拮抗剂制剂，作为第一个获得 FDA 批准的制剂治疗糖尿病神经病变。