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

摘要 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，其特征在于： 外周神经内甲状腺素运载蛋白（TTR）蛋白的异常细胞外沉积（ATTR-PN）和/或 在心脏内（ATTR-CM）。有两种类型的ATTR：（1）遗传性ATTR（hATTR），其中不稳定的 TTR基因中的突变是遗传的，或（2）ATTRwt，其中具有野生型TTR基因序列的人 偶尔发病。最近的估计将全球受ATTR影响的人数定为 大约55万。然而，这些患者人群被认为是明显诊断不足， 缺乏快速和容易获得的诊断方法。 需要新的ATTR疾病诊断方法，因为ATTR的确认很慢，需要5年时间。许多患者 出现可归因于其他疾病的症状，导致误诊。因此，ATTR 通常通过排除其他疾病的过程来诊断，许多患者不得不看多个专家 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 一旦被诊断患有ATTR，预期寿命只有2-10年，基于血液的诊断和生物标志物可以 用于将当前的范式从晚期沉积的确认转变为临床水平的筛查， 有疑似风险的个体更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，诊断生物标志物在确定疗效方面将是非常宝贵的。 已被证明对患者具有可变的长期结果的治疗药物。这将允许 医生指导患者接受最具成本效益和适当的批准药物治疗， 条件 从正常TTR到淀粉样蛋白沉积的途径通过单体中间体进行， 疾病风险和进展的生物标志物。所提出的基于血液的诊断是专门为 使用新的、超罕见的抗体检测TTR单体，这些抗体已经被发现，并且将是快速、灵敏的， 并且是非侵入性的。在第1阶段，将生成初始概念验证数据，以显示TTR升高 与正常健康供体相比，诊断为ATTR的患者中的单体。如果成功，这将是 这是第一个基于血液的疾病诊断商业化的第一步。

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.