Analytical Validation of Non-native Transthyretin (NNTTR) As A Candidate Biomarker for Transthyretin Amyloidoses (ATTR)

非天然转甲状腺素蛋白 (NNTTR) 作为转甲状腺素蛋白淀粉样变性 (ATTR) 候选生物标志物的分析验证

• 批准号: 10357108
• 负责人: Xin Jiang
• 金额: $ 136.81万
• 依托单位: PROTEGO BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10357108
• 关键词: Address; Affect; Age; Alzheimer' s Disease; Amyloid; Amyloid deposition; Amyloidosis; Antibodies; Appearance; Binding; Biological; Biological Assay; Biological Markers; Biopsy; Brain; Carrier Proteins; Central Nervous System Diseases; Cerebrospinal Fluid; Characteristics; Clinical; Clinical Drug Development; Clinical Trials; Collection; Congo Red; Coupled; Deposition; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Dissociation; Early Diagnosis; Early treatment; Ensure; Enzyme-Linked Immunosorbent Assay; Equipment and supply inventories; Familial Amyloid Neuropathies; Gender; Genes; Genetic Carriers; Genotype; Goals; Human; Immunoassay; Laboratories; Lead; Liver; Measurable; Measurement; Measures; Medical; Methods; Molecular; Molecular Conformation; Monitor; Mutation; Nature; Neuraxis; Organ; Outcome; Pathogenicity; Pathologic; Pathology; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phase; Phenotype; Plasma; Polyneuropathy; Population Group; Prealbumin; Prevention; Procedures; Process; Production; Progressive Disease; Protocols documentation; Qualifying; Quality of life; Reagent; Recovery; Reference Standards; Reporting; Retina; Sampling; Small Interfering RNA; Specific qualifier value; Specificity; Standardization; Structure; Structure of choroid plexus; Symptoms; Testing; Therapeutic; Thyroxine; TimeLine; Tissue Stains; Tissues; Validation; Variant; abeta accumulation; amyloid formation; antibody detection; body system; candidate marker; clinical Diagnosis; clinical decision-making; clinical development; commercialization; deprivation; design; drug development; early detection biomarkers; experimental study; genetic testing; healthy volunteer; human tissue; improved; liver transplantation; meetings; method development; mutant; neurotoxicity; next generation; non-Native; pharmacodynamic biomarker; prototype; public health relevance; response; targeted treatment; therapeutic target; validation studies

Project Description The transthyretin (TTR) Amyloidoses (ATTR) are progressive fatal diseases caused by the misfolding, aggregation and deposition of mutant and wild-type forms of TTR, a homotetrameric thyroxin transporting protein secreted by the liver, choroid plexus and retina. ATTR presenting as primary polyneuropathy (FAP) can affect the peripheral, autonomic and central nervous systems (CNS). It is traditionally diagnosed by clinical observation, Congo red staining of tissue biopsies, coupled with genetic testing. ATTR-FAP is widely underdiagnosed. ATTR-FAP patients commonly have a 2-3-year gap between first symptoms and diagnosis. ATTR affecting the CNS is difficult to diagnose and is often ignored or misdiagnosed. Recent advances in the development and commercialization of disease modifying therapeutics targeting ATTR underline the need for early and specific diagnosis. It is clear from current studies that early detection and treatment of ATTR and other amyloid diseases leads to superior clinical outcomes, as measured by arrest of disease progression and improved quality of life. As much desirable as is to treat the mutations, in practice, it is imperative to implement a objective initiation point for early treatment. Clinical trials targeting ATTR-FAP have employed relatively coarse clinical measures of peripheral nerve function which change relatively slowly requiring 12-24 months of observation to see measurable efficacy. The drug development process would be significantly shortened by monitoring the level of a pathologically related, quantifiable, pharmacodynamic biomarker. As with the Aβ aggregation seen in Alzheimer’s disease, misfolding/aggregation of TTR occur years before the emergence of symptoms and detectable amyloid formation. These distinctive circulating non-native TTR (NNTTR) structures are believed to be the proximal pathogenetic molecules producing neurotoxicity and tissue damage, making them ideal candidate biomarkers for early patient identification, and as a pharmaco- dynamic marker to monitor disease progression and drug response. We have developed a sandwich ELISA assay using proprietary antibodies specific for NNTTR. We have shown that the NNTTR immunoassay can rapidly and accurately identify pre-symptomatic carriers and V30M-TTR (most common mutation) and other ATTR-FAP patients using plasma and cerebrospinal fluid (CSF) samples. NNTTR levels are increased in plasma of pre-symptomatic carriers before symptom onset and are reduced in patients receiving different classes of ATTR therapeutics. Herein, we propose to conduct a full analytical validation of the NNTTR candidate biomarker, aiming at developing a robust quantitative measurement of NNTTR. If we are successful, further clinical validation and qualification will be pursued. The resulting NNTTR biomarker/assay can be used as an early diagnostic to specifically identify patients who can benefit from targeted ATTR therapeutics, such as tafamidis, patisiran, and inotersen, as well as additional ATTR therapeutics, currently in development, that may be more effective in the treatment and prevention of CNS disease.

项目描述 甲状腺素运载蛋白（TTR）淀粉样变性（ATTR）是由错误折叠引起的进行性致命疾病， TTR的突变体和野生型形式的聚集和沉积，TTR是一种同源四聚体甲状腺素转运蛋白， 由肝脏、脉络丛和视网膜分泌的蛋白质。ATTR表现为原发性多发性神经病（FAP）， 影响外周、自主神经和中枢神经系统（CNS）。传统上通过临床诊断 观察，刚果红染色组织活检，加上基因检测。ATTR-FAP广泛应用于 诊断不足ATTR-FAP患者在首次症状和诊断之间通常有2-3年的间隔。 影响CNS的ATTR很难诊断，经常被忽视或误诊。的最新进展 靶向ATTR的疾病修饰治疗剂的开发和商业化强调了以下需要： 早期特异性诊断。从目前的研究中可以清楚地看出，ATTR的早期发现和治疗， 其他淀粉样蛋白疾病导致上级临床结果，如通过阻止疾病进展所测量的， 改善生活质量。尽管处理突变是非常可取的，但在实践中， 早期治疗的客观起点。针对ATTR-FAP的临床试验已经采用了相对 外周神经功能的粗略临床测量，其变化相对缓慢，需要12-24个月的 观察以观察可测量的功效。药物开发过程将大大缩短， 监测病理学相关的、可量化的药效学生物标志物的水平。 与阿尔茨海默病中的Aβ聚集一样，TTR的错误折叠/聚集发生在几年后。 在出现症状和可检测到的淀粉样蛋白形成之前。这些独特的循环非本地 TTR（NNTTR）结构被认为是产生神经毒性的近端致病分子， 组织损伤，使其成为早期患者识别的理想候选生物标志物，并作为药物， 用于监测疾病进展和药物反应的动态标记物。我们开发了夹心ELISA 使用NNTTR特异性专有抗体进行测定。我们已经表明，NNTTR免疫测定可以 快速准确地识别症状前携带者和V30 M-TTR（最常见的突变）和其他 使用血浆和脑脊液（CSF）样本的ATTR-FAP患者。NNTTR水平增加， 在症状发作前，症状前携带者的血浆中， ATTR疗法的种类。在此，我们建议对NNTTR进行全面的分析验证 候选生物标志物，旨在开发NNTTR的稳健定量测量。如果我们成功了， 将进行进一步的临床验证和鉴定。所得NNTTR生物标志物/测定可用于 作为早期诊断，以特异性识别可从靶向ATTR治疗中获益的患者， 如tafamelatin、patisiran和inotersen，以及目前正在开发的其他ATTR治疗剂， 可能更有效地治疗和预防CNS疾病。