Development of a peptide-based diagnostic for amyotrophic lateral sclerosis

开发基于肽的肌萎缩侧索硬化症诊断方法

• 批准号: 9906532
• 负责人: Shrikumar Ambujakshan Nair
• 金额: $ 29.98万
• 依托单位: AFFINERGY, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-15 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906532
• 关键词: ALS patients; Accounting; Adult; Affect; Affinity; Age; American; Amyotrophic Lateral Sclerosis; Antibodies; Autoantibodies; Bacteriophages; Binding; Biological Markers; Blood; Breathing; Cessation of life; Classification; Clinical; Clinical Trials; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Marker; Disease Progression; Early Diagnosis; Ethnic Origin; Hyperthyroidism; Immobilization; Immunoglobulin A; Immunoglobulin M; Immunoglobulins; In Vitro; Individual; Inherited; Intervention; Intravenous Drug Abuse; Magnetic Resonance Imaging; Measures; Methods; Monitor; Motor Neurons; Multiple Sclerosis; Nerve; Neurologist; Neuromuscular Junction Diseases; Neurons; Patient-Focused Outcomes; Patients; Peptides; Performance; Peripheral Nervous System Diseases; Phage Display; Phase; Primary Care Physician; Production; Quality of life; Race; Rare Diseases; Research; Sampling; Sensitivity and Specificity; Serum; Severity of illness; Stress; Survival Rate; Symptoms; Technology; Testing; Time; Urine; Validation; base; care providers; commercialization; cost effective; disability; improved; multiple sclerosis patient; neuroinflammation; next generation sequencing; novel; novel marker; prognostic; progression marker; prospective; protein aminoacid sequence; prototype; rapid diagnosis; scale up; sex

SUMMARY/ABSTRACT Amyotrophic lateral sclerosis (i.e. ALS or Lou Gehrig's disease) is the most common adult-onset motor neuron disorder, with progressive weakness being the clinical hallmark. The average survival rate is 2-5 years post- diagnosis, but 10% of individuals survive ≥10 years, due to highly variable rates of progression. There is no cure for ALS, but there are treatments and interventions that can limit symptoms and unnecessary complications, and improve quality of life. Unfortunately, there is no single definitive diagnostic for ALS or validated biomarker for disease progression. It takes nearly a year from the first occurrence of symptoms to confirm ALS in most patients using current approaches (e.g. MRI, nerve function analyses, multiple blood and urine tests to rule out mimic disorders). Also, the only validated markers of disease progression are time to death and the Revised ALS Functional Rating Scale (ALSFRS-R), which is a subjective measure of disability and breathing. Although ALS is a rare disease (affecting approximately 20,000 people in the US), many more prevalent diseases can mimic ALS including but not limited to peripheral neuropathies, multiple sclerosis, neuromuscular transmission disorders, and hyperthyroidism. Significantly, up to 61% of ALS patients are misdiagnosed with a mimic disorder initially, which can negatively impact patient outcomes. There is an urgent unmet need to diagnose ALS at earlier timepoints via rapid and non-invasive methods, and to objectively predict ALS progression, particularly in the clinical trial setting. ALS-associated antibodies offer a new avenue for ALS diagnostics and disease monitoring. While previous studies measuring total levels of humoral antibody types (IgG, IgA, and IgM) have been inconsistent, recent studies have identified specific IgG autoantibodies, independent of absolute IgG level, as potential new markers of sporadic ALS onset and progression. Based on these recent findings, we propose to identify a sensitive and selective immunosignature, which we will develop into a reliable, non-invasive, in vitro array for the early detection of ALS. This array may also have potential for monitoring and predicting disease progression. In this Phase 1 application, we will use phage display biopanning and next generation sequencing to identify peptides that bind antibodies specifically enriched in patients with sporadic ALS and develop a peptide array capable of reproducibly detecting this immunosignature from serum. In Phase 2, we will refine the immunosignature for the early detection of ALS at baseline and additional timepoints, assess utility of the array to determine progression of the disease, and scale up array production. This simple peptide-based test will provide clear and actionable results for primary care physicians and neurologists, allowing the definitive and rapid diagnosis of ALS, thereby increasing the rate of early detection, diagnosis, and proper management. This test also has potential to enable the serum-based prediction of disease progression.

总结/摘要 肌萎缩侧索硬化症（即ALS或Lou Gehrig病）是最常见的成人发病运动神经元 疾病，进行性虚弱是临床标志。术后平均生存率为2-5年。 诊断，但10%的人生存≥10年，由于高度可变的进展率。无法治愈 对于ALS，但有治疗和干预措施可以限制症状和不必要的并发症， 提高生活质量。不幸的是，目前还没有ALS的单一明确诊断或有效的生物标志物， 疾病进展。大多数患者从首次出现症状到确诊ALS需要近一年时间 使用当前的方法（例如MRI，神经功能分析，多种血液和尿液测试以排除模拟 疾病）。此外，唯一经过验证的疾病进展标志物是至死亡时间和修订的ALS评分。 功能评定量表（ALSFRS-R），是残疾和呼吸的主观测量。虽然ALS 是一种罕见的疾病（在美国影响大约20，000人），许多更流行的疾病可以模仿 ALS包括但不限于周围神经病变、多发性硬化、神经肌肉传递 疾病和甲状腺功能亢进症。值得注意的是，高达61%的ALS患者被误诊为模仿性疾病， 最初，这可能会对患者的结果产生负面影响。有一个迫切的未满足的需要，诊断ALS在早期 通过快速和非侵入性的方法，客观地预测ALS的进展，特别是在 临床试验设置。ALS相关抗体为ALS诊断和疾病监测提供了新的途径。 虽然以前的研究测量体液抗体类型（IgG，伊加和IgM）的总水平， 不一致的是，最近的研究已经确定了特异性IgG自身抗体，独立于绝对IgG水平， 散发性ALS发病和进展的潜在新标志物。根据这些最新发现，我们建议 确定一个敏感的和选择性的免疫特征，我们将发展成为一个可靠的，非侵入性的， 用于ALS早期检测的体外阵列。该阵列还具有监测和 预测疾病进展。 在这个第一阶段的应用中，我们将使用噬菌体展示生物淘选和下一代测序来鉴定 结合散发性ALS患者中特异性富集的抗体的肽，并开发肽阵列 能够从血清中可重复地检测该免疫特征。在第二阶段，我们将完善 在基线和其他时间点早期检测ALS的免疫特征，评估阵列的效用 以确定疾病的进展，并扩大阵列生产。这个简单的肽基测试将 为初级保健医生和神经科医生提供明确和可操作的结果， ALS的快速诊断，从而提高早期发现，诊断和适当管理的比率。这 检测也有可能使基于血清的疾病进展的预测。