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.

摘要 PTI正在开发PTI-125-DX，这是一种新型的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诊断方法， 特别是能够检测出认知障碍之前的早期病理变化的人， 症状PTI-125-DX测量血浆中两种蛋白质片段的比例， 我们的治疗候选物PTI-125的伴随诊断/生物标志物。PTI-125干扰和 阻止细丝蛋白A（FLNA）与α7-烟碱乙酰胆碱受体（α 7 nAChR）的结合， 淀粉样蛋白β 1-42（Aβ42）被劫持以过度磷酸化tau蛋白。我们已经测试了 220份血浆样本，并显示两个数量级的患者之间的显着差异 AD诊断（通过影像学或CSF标志物证实）和年龄匹配的正常对照。 这两个组的区分具有98-100%的准确性。在两项设盲研究之一中，PTI- 125-DX将具有确诊AD病理学的MCI（MCI-AD）与具有疑似非AD病理学的MCI区分开。 淀粉样蛋白病理学（MCI-SNAP）的准确率为92%;在另一个，这种区分需要 通过成像确认。在本提案中，我们将比较额外的MCI-AD和MCI-SNAP 样本，并通过检测来自以下样本的存档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、早发性家族性AD（FAD）、癌症和老年人或年轻人一起 对照由于PTI-125-DX目前为蛋白质印迹形式，我们将开发ELISA测定法， 将其与使用ProteinSimple's Wes™的自动Western印迹格式进行比较。在第二阶段，我们将 通过用精心选择的肽和重组体免疫产生专有抗体， 这些多克隆抗体将被筛选和测试，以确定最佳的 组合。然后将相应的免疫原用于开发单克隆抗体。 抗体的我们设想的夹心ELISA将捕获所有感兴趣的片段， 检测两个特定的蛋白质片段。最终单克隆抗体和最终ELISA（或Wes） 选择格式后，我们将对多达250份去识别血浆样本进行新的设盲研究 来自Aibl研究。在这项工作结束时，PTI-125-DX将准备就绪， 商业化或合作。