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

神经性蜡样脂褐质病（NCL）的治疗途径正在迅速扩大。ncl是一种罕见的、破坏性的、主要影响儿童的神经退行性溶酶体贮积性疾病。青少年NCL （CLN3疾病）是最普遍的形式，具有一系列复杂的多域体征和症状，可在20年内逐渐发展并最终导致过早死亡。目前，还没有批准的疾病改善疗法。该提案将促进NCL研究的国际领导者，罗切斯特大学（罗切斯特，纽约）和汉堡大学（汉堡，德国）之间的合作。这种多中心、多国合作关系反映了临床试验实施的未来模式，并为开发CLN3疾病的新疗法奠定了基础。该提案将解决CLN3疾病临床试验设计和实施的关键挑战：优化敏感的临床评估，测量患者的感觉和功能，验证2期试验中早期疗效读数的决策，并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)完善系统和全面评估CLN3疾病的方法，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2期试验中疾病进展的生物标志物；3)为临床结果评估工具的可重复多地点使用做准备。在授予期间，我们将与美国食品和药物管理局合作进行临床结果评估和生物标志物鉴定过程，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.