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

PHS 2019-02 NIH、CDC 和 FDA 小型企业创新研究补助金申请综合征集（母公司 SBIR [R43/R44] 不允许临床试验

• 批准号: 10269937
• 负责人: Todd Levine
• 金额: $ 119.81万
• 依托单位: CND LIFE SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10269937
• 关键词: Affect; Age; Algorithms; Applications Grants; Biopsy; Blinded; Centers for Disease Control and Prevention (U.S.); Cerebellar Ataxia; Cessation of life; Characteristics; Clinical; Clinical Data; Cutaneous; Data; Dementia with Lewy Bodies; Deposition; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Early Diagnosis; Essential Tremor; Evaluation; Goals; Grant; Individual; Laboratories; Lead; Life; Location; Measurement; Measures; Medical; Multiple System Atrophy; Nerve Fibers; Nervous system structure; Neurodegenerative Disorders; Parents; Parkinson Disease; Pathologic; Patients; Peripheral Nervous System; Phase; Physicians; Progressive Supranuclear Palsy; Pure Autonomic Failures; Research Project Grants; Sampling; Sensitivity and Specificity; Series; Skin; Small Business Innovation Research Grant; Subgroup; Surrogate Endpoint; Symptoms; Testing; Time; Tissues; Translations; United States; United States National Institutes of Health; accurate diagnosis; accurate diagnostics; alpha synuclein; clinical Diagnosis; clinical practice; cohort; cost effective; diagnostic biomarker; disability; innovation; motor symptom; prospective; public health relevance; sex; synuclein; synucleinopathy; tissue biomarkers; tool; treatment trial

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.

项目摘要/摘要：突触核蛋白病是一组由以下原因引起的神经退行性疾病： 磷酸化（病理性）α-突触核蛋白在中枢和周围神经系统内的沉积。 突触核蛋白病影响美国超过 200 万人，包括帕金森病、多种 系统萎缩、路易体痴呆和纯粹的自主神经衰竭。目前临床诊断为 是在疾病晚期进行的，具有中等的敏感性和特异性。有紧急未得到满足的医疗 需要更好的诊断测试。该项目的长期目标是带来最新的关键科学成果 关于皮肤磷酸化 α-突触核蛋白沉积的发现进入临床实践。近期目标 该提案的目的是验证客观病理学测试作为突触核蛋白病的诊断标志物 定义测试的准确性、精密度、灵敏度和特异性，并迈出区分的第一步 突触核蛋白病之间。在大量初步数据的支持下，该项目的中心里程碑是 确定测量标准穿孔皮肤活检中的磷酸化 α-突触核蛋白沉积将起到作用 作为突触核蛋白病的准确、精确、敏感和特异的诊断生物标志物。这样做的理由 建议是有效的组织标记物 (1) 将提供 α- 的准确和早期诊断 临床实践中的突触核蛋白病； (2) 将能够评估发展中的目标参与度 疾病缓解和神经保护疗法； （3）将加速神经保护领域的发展 和疾病修饰疗法。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 通过以下具体目标： (1) 明确皮肤活检检测的测试准确度和精密度 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 -突触核蛋白沉积用于诊断突触核蛋白病和 (3) 区分 通过定量测量皮肤活检中的磷酸化 α-突触核蛋白来诊断突触核蛋白病 与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 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对活检结果不知情的疾病专家小组进行确认，而活检 磷酸化 α-突触核蛋白的免疫染色将不了解临床状态。在目标 1-3 结束时， 我们将通过定义 (1) 准确性和来验证磷酸化 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 突触核蛋白病。这些结果将加速磷酸化α-皮肤活检检测的转化 突触核蛋白成为医生和患者临床上可用的、具有成本效益且准确的诊断工具。这 通过准确、快速的临床诊断工具的开发将是该领域的垂直进步 诊断并促进潜在的神经保护和疾病改变治疗试验的进展。