Development of PTI-125-DX, a blood-based diagnostic for Alzheimer's disease

开发阿尔茨海默病的血液诊断剂 PTI-125-DX

• 批准号: 9758123
• 负责人: Lindsay H Burns
• 金额: $ 110.97万
• 依托单位: CASSAVA SCIENCES, INC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9758123
• 关键词: Affinity; Age; Alleles; Alzheimer' s Disease; Alzheimer’s disease biomarker; Amyloid beta-Protein; Antibodies; Antibody Formation; Antigens; Archives; Autopsy; Binding; Biological Assay; Blinded; Blood; Brain; Brain Diseases; Clinical Trials; Dementia; Dependence; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Dot Immunoblotting; Early Onset Familial Alzheimer' s Disease; Elderly; Enzyme-Linked Immunosorbent Assay; Epitopes; Frontotemporal Dementia; Genotype; Hippocampus (Brain); Hybridomas; Image; Immune Sera; Immunize; Immunoglobulin G; Institutional Review Boards; Lead; Length; Lewy Body Dementia; Malignant Neoplasms; Measures; Molecular Conformation; Monoclonal Antibodies; Mus; Mutation; Neurobehavioral Manifestations; Oryctolagus cuniculus; Pain; Parkinson Disease; Pathologic; Pathology; Patients; Peptide Fragments; Peptides; Phase; Plasma; Positron-Emission Tomography; Production; Protein Fragment; Protocols documentation; Recombinant Proteins; Recombinants; Sampling; Slice; Small Business Technology Transfer Research; Specificity; Testing; Therapeutic; Time; Tissues; Western Blotting; Work; alpha-bungarotoxin receptor; base; clinical Diagnosis; commercialization; companion diagnostics; diagnostic biomarker; disease diagnosis; filamin; fluorodeoxyglucose positron emission tomography; hyperphosphorylated tau; interest; mild cognitive impairment; monoclonal antibody production; novel; polyclonal antibody; prevent; small molecule therapeutics; tau Proteins; therapeutic candidate

Abstract PTI is developing PTI-125-DX, a novel, quantitative blood-based diagnostic candidate for Alzheimer's disease (AD). A non-invasive and inexpensive AD diagnostic is sorely needed, particularly one with the ability to detect early pathological changes that precede cognitive symptoms. PTI-125-DX measures the ratio of two protein fragments in plasma and is a companion diagnostic/biomarker for our therapeutic candidate PTI-125. PTI-125 disrupts and prevents filamin A (FLNA)'s association with the α7-nicotinic acetylcholine receptor (α7nAChR), which amyloid beta 1-42 (Aβ42) hijacks to hyperphosphorylate tau protein. We have tested over 220 plasma samples and show two orders of magnitude significant differences between patients with AD diagnoses (confirmed by imaging or CSF markers) and age-matched normal controls. These two groups are distinguished with 98-100% accuracy. In one of two blinded studies, PTI- 125-DX distinguished MCI with confirmed AD pathology (MCI-AD) from MCI with suspected non- amyloid pathology (MCI-SNAP) with 92% accuracy; in the other, this distinction needs confirmation by imaging. In this proposal, we will compare additional MCI-AD and MCI-SNAP samples and determine disease specificity of the assay by testing archived plasma samples from patients with dementia with Lewy bodies, Frontotemporal Dementia and Parkinson's disease alongside AD, MCI-AD, MCI-SNAP, early-onset familial AD (FAD), cancer and elderly or young controls. As PTI-125-DX is currently in Western blot format, we will develop an ELISA assay and compare it to an automated Western blot format using ProteinSimple's Wes™. In Phase II, we will generate proprietary antibodies by immunizing with carefully selected peptides and recombinant proteins; these polyclonal antibodies will be screened and tested to determine optimal combinations. The corresponding immunogens will then be used to develop monoclonal antibodies. The sandwich ELISA we envision will capture all fragments of interest and separately detect two specific protein fragments. With final monoclonal antibodies and a final ELISA (or Wes) format selected, we will perform a new blinded study of up to 250 de-identified plasma samples from the AIBL study. At the conclusion of this work, PTI-125-DX will be ready for commercialization or partnering.

抽象的 PTI 正在开发 PTI-125-DX，这是一种新型定量血液诊断候选药物 阿尔茨海默病（AD）。迫切需要一种非侵入性且廉价的 AD 诊断， 特别是能够检测出认知之前的早期病理变化的能力 症状。 PTI-125-DX 测量血浆中两个蛋白质片段的比例，是一种 我们的候选治疗药物 PTI-125 的伴随诊断/生物标志物。 PTI-125 扰乱和 防止细丝蛋白 A (FLNA) 与 α7-烟碱乙酰胆碱受体 (α7nAChR) 的结合， 淀粉样蛋白 β 1-42 (Aβ42) 劫持使 tau 蛋白过度磷酸化。我们已经测试过 220 个血浆样本并显示患者之间存在两个数量级的显着差异 具有 AD 诊断（通过影像学或脑脊液标记物证实）和年龄匹配的正常对照。 这两组的区分准确度为 98-100%。在两项盲法研究之一中，PTI- 125-DX 将已确诊 AD 病理的 MCI (MCI-AD) 与疑似非 AD 病理的 MCI 区分开来 淀粉样蛋白病理学 (MCI-SNAP) 准确率达 92%；另一方面，这种区别需要 通过影像学证实。在本提案中，我们将比较额外的 MCI-AD 和 MCI-SNAP 样本并通过测试存档的血浆样本来确定测定的疾病特异性 路易体痴呆、额颞叶痴呆和帕金森病患者 与 AD、MCI-AD、MCI-SNAP、早发家族性 AD (FAD)、癌症以及老年人或年轻人一起 控制。由于 PTI-125-DX 目前采用蛋白质印迹格式，我们将开发 ELISA 测定法并 将其与使用 ProteinSimple 的 Wes™ 进行的自动化蛋白质印迹格式进行比较。在第二阶段，我们将 通过使用精心挑选的肽和重组体进行免疫来产生专有抗体 蛋白质；这些多克隆抗体将经过筛选和测试以确定最佳 组合。然后相应的免疫原将用于开发单克隆抗体 抗体。我们设想的夹心 ELISA 将捕获所有感兴趣的片段并分别 检测两个特定的蛋白质片段。使用最终的单克隆抗体和最终的 ELISA（或 Wes） 选择格式后，我们将对多达 250 个未识别的血浆样本进行新的盲法研究 来自 AIBL 研究。这项工作完成后，PTI-125-DX 将准备好 商业化或合作。