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

项目总结 肌萎缩侧索硬化症领域的治疗开发努力面临的一个主要挑战是 开始治疗的疾病。虽然原因很复杂，但有一个非常重要的原因 因素是，几乎可以肯定的是，疾病过程早在最早的临床表现之前就开始了 在症状出现时运动神经元显著丧失的疾病，到症状出现时更是如此 诊断(通常在症状出现约一年后进行)。我们长期以来一直主张这样一种想法 早期的治疗性试验，甚至是预防性试验，将提供更大的成功可能性，并可能 在肌萎缩侧索硬化症的风险人群中进行。然而，在考虑这样一项试验时，我们认识到， 了解肌萎缩侧索硬化症的症状前阶段，包括试验设计的关键因素。这促使我们 发起(2007年)Pre-FALS(无症状家族性肌萎缩侧索硬化症)，一项纵向自然病史和生物标记物研究 是ALS相关基因突变携带者的症状前个体；他们目前是 只有已知的ALS高危人群，并且可以考虑对有症状前疾病进行研究。 在过去的10年里，我们开发和完善了筛选和招生的方法 可能有患肌萎缩侧索硬化症风险的个人；提供症状前的遗传咨询和检测； 保持纵向随诊，随诊损失最小。在这样做的过程中，我们逐步扩大了 FALS前队列包括113名基因阳性者，共积累~447人-- 数年的随访；这些患者中有14人进展到临床表现疾病，估计产生了 两年的平均表观转化率约为10%。手头有重要的初步数据和运营情况 基础设施已经到位，我们准备扩大FALS前队列，显著延长累积 后续时间，预计在赠款周期结束时总共观察到约45次表型转化事件。 采用多模式的评估程序阵列，包括‘湿’和‘干’生物标记物， 允许对疾病的亚临床症状进行量化，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，我们将确定是否有可能 确定ALS遗传风险的一部分人，这些人具有足够高的短期发展风险 风险的降低可以用来为疾病预防试验提供足够的动力。第二，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 生物标记物可以用来量化实验性疗法对疾病的生物学影响 预防试验。这些数据和我们在疾病症状前期收集的洞察力将使我们能够 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 无论哪个治疗剂(S)最有希望，我们都准备启动一项开创性的试验 这种类型的。SOD1和C9orf72反义寡核苷酸可能是早期实验治疗的候选基因。

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.