Meaningful Outcomes and Multi-Site Readiness for Clinical Trials in Juvenile Neuronal Ceroid Lipofuscinosis

神经性蜡样脂褐素沉着症(NCL)的治疗管道正在迅速扩大。NCLS是一种罕见的、破坏性的、神经退行性的溶酶体储存障碍，主要影响儿童。青少年NCL(CLN3病)是最常见的一种类型，具有一套复杂的多领域体征和症状，在20年内逐渐发展，最终导致过早死亡。目前，还没有获得批准的疾病修正疗法。这项建议将促进NCL研究领域的国际领导者、罗切斯特大学(纽约罗切斯特)和汉堡大学(德国汉堡)之间的合作。这一多中心、多国家的合作伙伴关系反映了临床试验实施的未来模式，并为开发治疗CLN3疾病的新疗法奠定了基础。该提案将解决设计和实施CLN3疾病临床试验的关键挑战：优化衡量患者感觉和功能的敏感临床评估，验证第二阶段试验中进行不进行决策的早期读数，以及准备在多个临床试验地点进行严格和一致的疾病评估。同时，我们的目标是：1)改进对CLN3疾病进行系统和全面评估的方法，以便在未来的试验中最好地量化进展；2)验证定量脑神经成像测量作为第二阶段试验疾病进展的生物标志物的有效性；以及3)为临床结果评估工具的可重复使用做好准备。在获奖期间，我们将让食品和药物管理局参与临床结果评估和生物标记物资格鉴定过程，以确保为未来新出现的CLN3疾病治疗试验的监管审查过程做好最佳准备。

The neuronal ceroid lipofuscinosis (NCL) therapeutic pipeline is rapidly expanding. The NCLs are rare, devastating, neurodegenerative lysosomal storage disorders that mainly affect children. Juvenile NCL (CLN3 disease) is the most prevalent form, with a complex set of multi-domain signs and symptoms that gradually progress over 20 years and culminate in premature death. Currently, there are no approved disease-modifying therapies. This proposal will foster collaboration between international leaders in NCL research, the University of Rochester (Rochester, New York) and the University of Hamburg (Hamburg, Germany). This multi-center, multi-national partnership mirrors the future model for clinical trial implementation and lays the foundation for development of novel therapeutics for CLN3 disease. The proposal will address critical challenges for the design and implementation of clinical trials in CLN3 disease: optimizing sensitive clinical assessments that measure how patients feel and function, validating early readouts of efficacy for go-no go decision making in phase 2 trials, and preparing for rigorous and consistent disease evaluation across multiple clinical trial sites. In parallel, our aims are: 1) to refine approaches to systematic and comprehensive assessment of CLN3 disease in order to best quantify progression in future trials, 2) to validate quantitative brain neuroimaging measurements as biomarkers of disease progression for phase 2 trials, and 3) to prepare for reproducible multi-site use of clinical outcome assessment tools. During the award period, we will engage the Food and Drug Administration in clinical outcome assessment and biomarker qualification processes to ensure optimal preparation for future regulatory review processes for emerging CLN3 disease therapeutic trials.