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

基本信息

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
项目类别：
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

项目摘要

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其原因很复杂，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观点：早期的治疗甚至预防性试验将提供更大的成功可能性，并且可能然而，在考虑进行这样的试验时，我们认识到做得太少了。了解 ALS 的症状前阶段，包括对试验设计至关重要的要素。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；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；并保持纵向随访，将随访损失降到最低。通过这样做，我们逐渐扩大了范围。 Pre-fALS 队列包括 113 名基因阳性个体，总计约 447 人随访数年；其中 14 人已出现临床症状，估计已出现症状平均两年表型转化率约为 10%，手头有重要的初步数据和可操作的数据。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：对于未来疾病预防试验的设计至关重要，首先，我们将确定是否有可能确定具有 ALS 遗传风险的一小部分人，他们的短期发展风险足够高其次，我们将利用降低风险来充分推动疾病预防试验。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这些数据和我们对疾病症状前阶段收集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 SOD1 和 C9orf72 反义寡核苷酸可能是早期实验性治疗候选药物。