PHS 2019-02 Omnibus Solicitation of the NIH, CDC, and FDA for SmallBusiness Innovation Research Grant Applications (Parent SBIR [R43/R44] ClinicalTrial Not Allowed

项目摘要/摘要：突触核蛋白病是一组神经退行性疾病， 磷酸化（病理性）α-突触核蛋白在中枢和外周神经系统内的沉积。 突触核蛋白病影响美国超过200万人，包括帕金森病、多发性硬化症和帕金森病。 系统萎缩、路易体痴呆和单纯自主神经衰竭。目前临床诊断为 在疾病的晚期进行，具有中等的敏感性和特异性。有一个紧急的未满足的医疗 需要更好的诊断测试。该项目的长期目标是将最近的关键科学 关于皮肤磷酸化α-突触核蛋白沉积的发现应用于临床实践。这一近期目标 该建议的目的是通过以下方式验证作为突触核蛋白病诊断标志物的客观病理学测试： 确定检测的准确性、精密度、灵敏度和特异性，并在区分 突触核蛋白病之间的联系该项目的中心里程碑，得到广泛的初步数据的支持，是 确定在标准穿刺皮肤活检中测量磷酸化α-突触核蛋白沉积将有助于 作为突触核蛋白病的准确、精确、灵敏和特异的诊断生物标志物。这样做的理由 建议有效的组织标记物（1）将提供α-甲状腺癌的准确和早期诊断， 突触核蛋白病在临床实践中;（2）将能够评估目标参与的发展， 疾病修饰和神经保护疗法;（3）将加速神经保护疗法的发展 和疾病改善疗法。在强有力的初步数据的指导下，我们计划客观地检验我们的假设 通过以下具体目的：（1）明确皮肤活检检测的准确度和精密度， 磷酸化的α-突触核蛋白。(2)目的：探讨皮肤活检检测乳腺癌的敏感性和特异性。 磷酸化α -突触核蛋白沉积用于诊断突触核蛋白病和（3）区分 通过定量测量皮肤活检组织中磷酸化α -突触核蛋白， 结合临床数据的算法包含。我们将通过一个 对300名突触核蛋白病患者和200名对照受试者进行前瞻性横断面评估。 突触核蛋白病状态将由一组对活检结果不知情的疾病专家确认， 磷酸化α-突触核蛋白的免疫染色将对临床状态设盲。在目标1-3结束时， 我们将通过定义（1）准确性和（2）特异性来验证磷酸化α-突触核蛋白的皮肤活检检测。 精确度，（2）灵敏度和特异性，以及（3）采取第一步来区分 共核蛋白病这些结果将加速翻译皮肤活检检测磷酸化α- 突触核蛋白转化为临床上可用的、成本有效的和准确的诊断工具，供医生和患者使用。的 这种诊断工具的开发将是该领域的垂直进步， 诊断和促进潜在的神经保护和疾病改善治疗试验的进展。

Project Summary / Abstract: Synucleinopathies are a group of neurodegenerative disorders that result from the deposition of phosphorylated (pathological) α-synuclein within the central and peripheral nervous systems. Synucleinopathies affect over 2 million people in the United States and include Parkinson disease, multiple system atrophy, dementia with Lewy bodies and pure autonomic failure. At present, the clinical diagnosis is made very late in the disease and with moderate sensitivity and specificity. There is an urgent unmet medical need for better diagnostic testing. The long-term goal of this project is to bring recent critical scientific discoveries about cutaneous phosphorylated α-synuclein deposition into clinical practice. The immediate goal of this proposal is to validate an objective pathological test as a diagnostic marker for synucleinopathies by defining the accuracy, precision, sensitivity and specificity of testing and to take a first step in differentiating between synucleinopathies. The central milestone of this project, supported by extensive preliminary data, is to establish that measuring phosphorylated α-synuclein deposition in standard punch skin biopsies will serve as an accurate, precise, sensitive and specific, diagnostic biomarker of synucleinopathy. The rationale for this proposal is that an effective tissue marker (1) will provide an accurate and early diagnosis of alpha- synucleinopathies in clinical practice; (2) will enable assessment of target engagement in the development of disease modifying and neuroprotective therapies; and (3) will accelerate the development of neuroprotective and disease modifying therapies. Guided by strong preliminary data, we plan to objectively test our hypothesis through the following specific aims: (1) To define the test accuracy and precision of skin biopsy detection of phosphorylated α-synuclein. (2) To define the sensitivity and specificity of skin biopsy detection of phosphorylated α -synuclein deposition for the diagnosis of synucleinopathies and (3) To differentiate between the synucleinopathies by quantitative measurement of phosphorylated α -synuclein within skin biopsies in combination with an algorithmic inclusion of clinical data. We will complete these specific aims through a prospective cross-sectional evaluation of 300 individuals with synucleinopathies and 200 control subjects. Synucleinopathy status will be confirmed by a panel of disease experts blinded to biopsy results, while biopsy immunostaining for phosphorylated α-synuclein will be blinded to clinical status. At the conclusion of Aims 1-3, we will have validated skin biopsy detection of phosphorylated α-synuclein by defining the (1) accuracy & precision, (2) sensitivity and specificity and (3) to take the first steps to differentiate between the synucleinopathies. These results will accelerate the translation of skin biopsy detection of phosphorylated α- synuclein into a clinically available, cost effective and accurate diagnostic tool for physicians and patients. The development of such a diagnostic tool will be a vertical advance in the field through accurate and rapid clinical diagnosis and by facilitating advances in potential neuroprotective and disease modifying treatment trials.