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

项目摘要 ALS领域中的疗法开发努力的主要挑战是治疗过程中的相对晚期阶段。 开始治疗的疾病。虽然原因很复杂，但一个至关重要的原因是， 因素是，疾病过程几乎肯定在最早的临床表现之前就开始了。 在症状发作时运动神经元显著丧失的疾病，在 诊断（通常在症状发作后约一年进行）。我们长期以来一直倡导这样一种观点， 早期的治疗，甚至是预防性的试验将提供更大的成功可能性， 在有ALS风险的人群中进行。然而，在考虑这样一个试验时，我们认识到， 了解ALS的症状前阶段，包括试验设计的关键要素。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风险的人群，可考虑对这些人群进行症状前疾病研究。 在过去的10年里，我们已经开发和完善了筛选和登记的方法， 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，将随访损失降至最低。在这样做的过程中，我们逐渐扩大了 Pre-fALS队列包括113个基因阳性个体，总共累积了约447人， 年随访;这些人中有14人已进展为临床表现疾病， 平均两年表型转化率约为10%。掌握了大量的初步数据， 基础设施现已到位，我们准备扩大预fals队列，显着延长累积 随访时间，并且可以预期在赠款周期结束时观察到总共约45个表型转化事件。 采用包括“湿”和“干”生物标志物的多模式评估程序阵列， 允许量化疾病的亚临床体征，我们将解决两个非常具体的问题， 这是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 确定一个有ALS遗传风险的人的子集，这些人有足够高的短期发展风险， 因此，风险的降低可以用来为疾病预防试验提供足够的动力。二是 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疾病中实验性治疗的生物学影响 预防试验。这些数据和我们对疾病症状前阶段的了解，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， 无论哪种治疗药物最有希望，我们都准备启动一项开创性的试验。 这一类的。SOD 1和C9 orf 72反义寡核苷酸可能是早期实验性治疗候选物。

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.