Pre-Symptomatic Familial ALS (Pre-fALS) Study - Prelude to a Treatment Trial; Administrative Supplement

症状前家族性 ALS (Pre-fALS) 研究 - 治疗试验的前奏；

• 批准号: 10363844
• 负责人: Michael Benatar
• 金额: $ 17.19万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10363844
• 关键词: Address; Administrative Supplement; Amyotrophic Lateral Sclerosis; Antisense Oligonucleotides; Biological; Biological Markers; C9ORF72; Clinical; Complex; DNA Sequence Alteration; Data; Diagnosis; Disease; Early intervention trials; Elements; Enrollment; Event; Future; Gene Mutation; Genes; Genetic Counseling; Genetic Risk; Glean; Grant; Hand; Individual; Infrastructure; Investigational Therapies; Knowledge; Methods; Motor Neurons; Natural History; Neurodegenerative Disorders; Persons; Phase; Population; Populations at Risk; Preparation; Prevention trial; Procedures; Process; Risk; Symptoms; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; base; cohort; design; disorder prevention; familial amyotrophic lateral sclerosis; follow-up; genetic testing; insight; multimodality; preventive intervention; screening; success; superoxide dismutase 1; therapeutic candidate; therapeutic development; therapy development; treatment trial; trial design

PROJECT SUMMARY A major challenge to therapy development efforts in the field of ALS is the relatively late stage in the course of the disease at which treatment is initiated. While the reasons for this are complex, one critically important factor is that the disease process almost certainly begins well before the earliest clinical manifestations of disease with significant loss of motor neurons by the time of symptom onset, and even more so by the time of diagnosis (which is typically made about a year after symptom onset). We have long championed the idea that an early therapeutic, or even a preventative, trial would offer much greater likelihood of success and could be undertaken in people at risk for ALS. In contemplating such a trial, however, we recognized that too little was known about the pre-symptomatic phase of ALS, including elements critical to trial design. This prompted us to initiate (in 2007) Pre-fALS (Pre-Symptomatic Familial ALS), a longitudinal natural history and biomarker study of pre-symptomatic individuals who are carriers of an ALS-associated gene mutation; they are currently the only known population at risk for ALS and in whom a study of pre-symptomatic disease may be considered. Over the course of the last 10 years, we have developed and refined methods for screening and enrolling individuals who may be at risk for developing ALS; providing pre-symptomatic genetic counseling and testing; and maintaining longitudinal follow-up with minimal loss to follow-up. In so doing, we have gradually expanded the Pre-fALS cohort to include 113 gene-positive individuals and have accumulated a total of ~447 person- years follow-up; 14 of these individuals have progressed to clinically manifest disease, yielding an estimated average two-year phenoconversion rate of ~10%. With significant preliminary data in hand and the operational infrastructure now in place, we are poised to expand the Pre-fALS cohort, significantly extend cumulative follow-up time and can expect to observe a total of ~45 phenoconversion events by the end of the grant cycle. Employing a multi-modal array of evaluative procedures that includes both ‘wet’ and ‘dry’ biomarkers which permit quantification of subclinical signs of disease, we will address two very specific questions that are fundamental to the design of a future disease prevention trial. First, we will determine whether it is possible to identify a subset of people at genetic risk for ALS who are at a sufficiently high-short term risk of developing disease that a reduction in risk could be used to adequately power a disease prevention trial. Second, we will quantify longitudinal trajectories of pre-symptomatic biomarkers to determine whether changes in these biomarkers could be used to quantify the biological impact of an experimental therapeutic in a disease prevention trial. These data and the insights we glean into the pre-symptomatic stage of disease, will enable us to design and implement a disease prevention or early intervention trial in the near future that could utilize whatever therapeutic agent(s) hold the most promise at the time we are ready to initiate a groundbreaking trial of this sort. SOD1 and C9orf72 antisense oligonucleotides are likely early experimental therapeutic candidates.

项目概要 ALS 领域的治疗开发工作面临的一个主要挑战是治疗过程中相对较晚的阶段。 开始治疗的疾病。虽然造成这种情况的原因很复杂，但其中一个至关重要 因素是，疾病过程几乎肯定早在最早的临床表现出现之前就开始了。 在症状出现时运动神经元明显丧失的疾病，在症状出现时更是如此 诊断（通常在症状出现一年左右进行）。我们长期以来一直倡导这样的想法： 早期的治疗甚至预防性试验将提供更大的成功可能性，并且可能 在有 ALS 风险的人群中进行。然而，在考虑进行这样的试验时，我们认识到，我们所做的努力太少了。 了解 ALS 症状前阶段，包括对试验设计至关重要的要素。这促使我们 启动（2007 年）Pre-fALS（症状前家族性 ALS），一项纵向自然史和生物标志物研究 症状前个体是 ALS 相关基因突变的携带者；他们目前是 仅已知有 ALS 风险且可考虑对症状前疾病进行研究的人群。 在过去 10 年中，我们开发并完善了筛选和注册方法 可能有患 ALS 风险的个人；提供症状前遗传咨询和检测； 保持纵向随访，将随访损失降到最低。在此过程中，我们逐渐扩大了 Pre-fALS 队列包括 113 名基因阳性个体，总计约 447 人 年随访；其中 14 人已发展为临床表现出的疾病，估计 平均两年表型转化率约为 10%。掌握了重要的初步数据和可操作的 基础设施现已到位，我们准备扩大 Pre-fALS 队列，显着延长累积 随访时间，预计在资助周期结束时观察到总共约 45 个表型转化事件。 采用多模式评估程序，包括“湿”和“干”生物标志物， 为了允许量化疾病的亚临床症状，我们将解决两个非常具体的问题： 对未来疾病预防试验的设计至关重要。首先我们要确定是否可以 确定具有 ALS 遗传风险的一小部分人，他们的短期发展风险足够高 疾病风险的降低可以用来充分推动疾病预防试验。其次，我们将 量化症状前生物标志物的纵向轨迹，以确定这些变化是否 生物标志物可用于量化实验疗法对疾病的生物学影响 预防试验。这些数据和我们收集到的疾病症状前阶段的见解将使我们能够 在不久的将来设计和实施疾病预防或早期干预试验，可以利用 当我们准备好启动突破性试验时，无论哪种治疗剂最有希望 这类的。 SOD1 和 C9orf72 反义寡核苷酸可能是早期实验性治疗候选药物。