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：联核病是一组由以下原因引起的神经退行性疾病 磷酸化的(病理性的)α-突触核蛋白在中枢和外周神经系统内的沉积。 联核病在美国影响着200多万人，包括帕金森病、多发性 系统萎缩，路易体痴呆和纯自主神经衰竭。目前，临床诊断为 发病很晚，具有中等的敏感性和特异度。有一份紧急的未得到满足的医疗报告 需要更好的诊断测试。该项目的长期目标是将最新的关键科学 皮肤磷酸化α-突触核蛋白沉积的发现进入临床实践。眼前的目标 这项建议的目的是验证客观病理测试作为联体核病的诊断标记物的有效性 确定检测的准确性、精密度、敏感性和特异性，并迈出区分的第一步 在联体核病之间。在大量初步数据的支持下，该项目的核心里程碑是 确定在标准的穿孔皮肤活检中测量磷酸化α-突触核蛋白沉积将起到作用 作为一种准确、精确、灵敏、特异的联核病诊断生物标志物。这样做的理由是 建议有效的组织标志物(1)将提供准确和早期的诊断 临床实践中的联合核病；(2)将能够评估目标参与发展 疾病修饰和神经保护疗法；以及(3)将加速神经保护的发展 以及治疗疾病的方法。在强劲的初步数据的指导下，我们计划客观地检验我们的假设 通过以下具体目标：(1)明确皮肤活检检测的准确性和精密度 磷酸化α-突触核蛋白。(2)明确皮肤活检检测的敏感性和特异性。 磷酸化α-突触核蛋白沉积对联核病的诊断和(3)鉴别 皮肤活检组织中磷酸化α-突触核蛋白定量检测与突触核病 与包含临床数据的算法相结合。我们将通过以下方式完成这些具体目标 300名联体核病患者和200名对照受试者的前瞻性横断面评估。 对活检结果视而不见的疾病专家小组将确认联核症状态，同时进行活检 对磷酸化α-突触核蛋白的免疫染色将对临床状态视而不见。在目标1-3结束时， 我们将通过定义(1)准确性来验证磷酸化α-突触核蛋白的皮肤活检检测。 精确度，(2)敏感性和特异性，以及(3)采取第一步来区分 联体核病。这些结果将加速皮肤活检检测磷酸化α- 将突触核蛋白转化为临床上可用的、具有成本效益且准确的诊断工具，供医生和患者使用。这个 这种诊断工具的开发将是该领域的垂直进步，通过准确和快速的临床 并通过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.