Development of a Blood-based Diagnostic for Early Detection of Transthyretin Amyloidosis

开发用于早期检测运甲状腺素蛋白淀粉样变性的基于血液的诊断方法

• 批准号: 10547120
• 负责人: MARCIN APOSTOL
• 金额: $ 27.03万
• 依托单位: ADRX, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2024-08-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547120
• 关键词: Address; Affect; Alzheimer' s Disease; Amyloid; Amyloid deposition; Amyloidosis; Antibodies; Biological Assay; Biological Markers; Biopsy; Blood; Blood specimen; Buffers; Clinical; Clinical Trials; Clinical Trials Design; Data; Deposition; Detection; Development; Diagnosis; Diagnostic; Diagnostic Trial; Disease; Disease Progression; Dissociation; Early Diagnosis; Early treatment; Enzyme-Linked Immunosorbent Assay; Functional disorder; Future; Genes; Heart; Heart failure; Human; Imaging Techniques; Individual; Inherited; Life Expectancy; Medical; Monitor; Monoclonal Antibodies; Mutation; Outcome; Patient Care; Patient Recruitments; Patient-Focused Outcomes; Patients; Peripheral Nerves; Persons; Pharmacotherapy; Phase; Physicians; Plasma; Play; Polyneuropathy; Prealbumin; Process; Proteins; Quality of life; Radionuclide Imaging; Rapid diagnostics; Recombinants; Reporting; Risk; Role; Sampling; Severity of illness; Specialist; Symptoms; Technology; Tissues; Treatment Efficacy; Treatment Protocols; Work; accurate diagnosis; base; blood-based biomarker; commercialization; cost effective; design; detection limit; diagnostic biomarker; diagnostic tool; disease diagnosis; disease diagnostic; disorder risk; drug efficacy; effective therapy; experience; extracellular; improved; monomer; mortality; noninvasive diagnosis; novel; novel diagnostics; novel therapeutics; patient population; rapid diagnosis; screening; single molecule; success

ABSTRACT Transthyretin amyloidosis (ATTR) is a rare, progressive, and ultimately fatal condition characterized by the abnormal extracellular deposition of transthyretin (TTR) protein within the peripheral nerves (ATTR-PN) and/or within the heart (ATTR-CM). There are two types of ATTR: (1) hereditary ATTR (hATTR), where the destabilizing mutation in the TTR-gene is inherited, or (2) ATTRwt, in which people with the wild-type TTR-gene sequence develop the disease sporadically. Recent estimates put the worldwide number of people affected by ATTR at approximately 550,000. However, these patient populations are thought to be significantly underdiagnosed, as there is a lack of rapid and readily available diagnostics. New diagnostics for ATTR disease are needed as confirmation of ATTR is slow, taking up 5 years. Many patients present with symptoms that can be attributed to other conditions, leading to misdiagnosis. Due to this, ATTR is often diagnosed by process of elimination of other diseases and many patients have to see multiple specialists before getting the correct diagnosis, causing a delay in treatment and further amyloid deposition. Given that the life expectancy once diagnosed with ATTR is only 2-10 years, a blood-based diagnostic and biomarker could be used to shift the current paradigm from confirmation of late-stage deposition to a clinical level screen, allowing an individual with suspected risk to receive disease-modifying treatment earlier, reducing mortality, and improving patient quality of life. Furthermore, a diagnostic biomarker will be invaluable in determining the efficacy of drugs for treatments which have been shown to have variable long-terms outcomes for patients. This will allow physicians to guide patients to the most cost effective and appropriate approved drug therapies for their condition. The path from normal TTR to amyloid deposition proceeds through a monomeric intermediate which can be a biomarker of disease risk and progression. The proposed blood-based diagnostic is designed specifically to detect the TTR monomer using novel, ultra-rare antibodies that have been discovered and will be rapid, sensitive, and non-invasive. In Phase 1, initial proof-of-concept data will be generated to show that there is elevated TTR monomers in patients diagnosed with ATTR compared to normal, healthy donors. If successful, this will be the first step towards the commercialization of the first blood-based diagnostic for the disease.

抽象的 甲状腺素运载蛋白淀粉样变性 (ATTR) 是一种罕见的、进行性的、最终致命的疾病，其特征是 周围神经内运甲状腺素蛋白 (TTR) 蛋白异常细胞外沉积 (ATTR-PN) 和/或 在心脏内（ATTR-CM）。 ATTR 有两种类型：(1) 遗传性 ATTR (hATTR)，其中不稳定因素 TTR 基因突变是遗传性的，或 (2) ATTRwt，其中具有野生型 TTR 基因序列的人 该病呈散发性发展。最近的估计表明，全球受 ATTR 影响的人数为 约550,000。然而，这些患者群体被认为诊断严重不足，因为 缺乏快速且容易获得的诊断方法。 由于 ATTR 的确认过程缓慢，需要 5 年时间，因此需要针对 ATTR 疾病的新诊断方法。很多病人 出现可归因于其他情况的症状，导致误诊。因此，ATTR 是 通常通过消除其他疾病的过程来诊断，许多患者必须去看多名专家 在得到正确的诊断之前，导致治疗延迟和进一步的淀粉样蛋白沉积。鉴于 一旦诊断出 ATTR，预期寿命只有 2-10 年，基于血液的诊断和生物标记物可能会 用于将当前范例从后期沉积确认转变为临床水平筛选，从而允许 疑似有风险的个体应尽早接受疾病缓解治疗，降低死亡率，以及 提高患者的生活质量。此外，诊断生物标志物对于确定疗效具有无价的价值。 用于治疗的药物已被证明对患者具有可变的长期结果。这将允许 医生指导患者采用最具成本效益和最合适的经批准的药物治疗 健康）状况。 从正常 TTR 到淀粉样蛋白沉积的路径通过单体中间体进行，该中间体可以是 疾病风险和进展的生物标志物。拟议的基于血液的诊断是专门设计的 使用已发现的新型、超稀有抗体检测 TTR 单体，该抗体将快速、灵敏、 并且非侵入性。在第一阶段，将生成初始概念验证数据以表明 TTR 有所提高 与正常健康供体相比，诊断为 ATTR 的患者的单体。如果成功的话，这将是 迈出了第一个基于血液的疾病诊断商业化的第一步。