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

症状前家族性 ALS (Pre-fALS) 研究 - 治疗试验的前奏

• 批准号: 10001608
• 负责人: Michael Benatar
• 金额: $ 55.27万
• 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/10001608
• 关键词: Address; Amyotrophic Lateral Sclerosis; Antisense Oligonucleotides; Biological; Biological Markers; C9ORF72; Clinical; Complex; DNA Sequence Alteration; Data; Diagnosis; Disease; Early intervention trials; Elements; Enrollment; Event; Familial Amyotrophic Lateral Sclerosis; 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; Preventive Intervention; Procedures; Process; Risk; Symptoms; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; base; cohort; design; disorder prevention; follow-up; genetic testing; insight; multimodality; 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.

项目摘要 在ALS领域的治疗发展工作的主要挑战是在此过程中的相对后期 开始治疗的疾病。虽然原因很复杂，但非常重要 因素是疾病过程几乎可以肯定始于最早的临床表现 疾病在症状发作时有明显的运动神经元丧失，甚至在 诊断（通常是在症状发作后一年大约进行的）。我们长期以来一直倡导 早期的理论，甚至是预防性试验，都将提供更大的成功可能性，并且可能是 在有ALS风险的人中进行。但是，在考虑这样的审判时，我们认识到太少了 有关ALS的症状前阶段的已知，包括对试验设计至关重要的元素。这促使我们 启动（2007年）前战前（症状前家族ALS），纵向自然史和生物标志物研究 症状前个体，这些个体是与ALS相关基因突变的载体；他们目前是 只有患有ALS风险的已知人群，并且可以考虑对症状前疾病的研究。 在过去的十年中，我们开发了筛选和注册的方法 可能有发展ALS风险的个人；提供症状前遗传咨询和测试； 并保持纵向随访，而随访的损失最小。这样，我们逐渐扩展 前战前队列包括113个基因阳性个体，总共积累了约447人 - 多年随访；这些人中有14个人已发展为临床表现疾病，估计 平均两年表现率约为10％。手头有大量的初步数据和操作 现在已经有了基础设施，我们被中毒以扩大前fals群体，显着扩展累积 随访时间，可以期望在赠款周期结束时观察到总共约45个表现事件。 采用包括“湿”和“干”的生物标志物在内的多模式的评估程序 允许疾病的亚临床迹象数量，我们将解决两个非常具体的问题 对于未来疾病预防试验设计的基础。首先，我们将确定是否有可能 确定对处于足够高的术语发展风险的ALS的遗传风险的一部分 可以使用降低风险的疾病来充分为疾病预防试验供电。第二，我们会的 量化症状前生物标志物的纵向轨迹，以确定这些纵向是否发生变化 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。这些数据以及我们将疾病症状的洞察力融入了疾病的症状，将使我们能够 在不久的将来设计和实施预防疾病或早期干预试验 无论您准备开始进行开创性试验时，什么治疗代理人拥有最大的承诺 这种。 SOD1和C9ORF72反义寡核苷酸可能是早期的实验治疗候选者。