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.

摘要/摘要 肌萎缩侧索硬化症（即 ALS 或卢伽雷氏病）是最常见的成人发病的运动神经元病 疾病，以进行性无力为临床标志，平均存活率为 2-5 年。 诊断，但由于进展率差异较大，10% 的个体存活 ≥10 年。 无法治愈。 对于 ALS，但有一些治疗和干预措施可以限制症状和不必要的并发症，并且 不幸的是，目前还没有针对 ALS 的单一明确诊断或经过验证的生物标志物。 大多数患者从首次出现症状到确诊需要近一年的时间。 使用当前的方法（例如 MRI、神经功能分析、多次血液和尿液测试来排除模仿） 此外，唯一经过验证的疾病进展标志物是死亡时间和修订版 ALS。 功能评定量表 (ALSFRS-R)，这是对 ALS 残疾和呼吸的主观测量。 是一种罕见疾病（影响美国大约 20,000 人），许多其他流行疾病可以模仿 ALS 包括但不限于周围神经病、多发性硬化症、神经肌肉传导病 值得注意的是，高达 61% 的 ALS 患者被误诊为拟态障碍。 早期诊断 ALS 的迫切需求尚未得到满足。 通过快速和非侵入性方法确定时间点，并客观预测 ALS 进展，特别是在 ALS 相关抗体的临床试验为 ALS 诊断和疾病监测提供了新途径。 虽然之前测量体液抗体类型（IgG、IgA 和 IgM）总水平的研究已 不一致的是，最近的研究已经确定了特定的 IgG 自身抗体，与绝对 IgG 水平无关，如 基于这些最新发现，我们建议散发性 ALS 发病和进展的潜在新标志物。 确定一种敏感且选择性的免疫特征，我们将其开发成一种可靠的、非侵入性的、 用于早期检测 ALS 的体外阵列 该阵列还可能具有监测和诊断的潜力。 预测疾病进展。 在此第一阶段应用中，我们将使用噬菌体展示生物淘选和下一代测序来识别 结合在散发性 ALS 患者中特异性富集的抗体的肽，并开发了肽阵列 能够从血清中重复检测这种免疫特征。在第二阶段，我们将完善该方法。 用于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，并扩大阵列生产规模，这种简单的基于肽的测试将。 为初级保健医生和神经科医生提供明确且可操作的结果，从而提供明确且可行的结果 快速诊断 ALS，从而提高早期发现、诊断和正确治疗的比率。 测试还有可能实现基于血清的疾病进展预测。