Multi-Site Validation of Biomarkers and Core Clinical Outcome Measures for Clinical Trials Readiness in CDKL5 Deficiency Disorder

CDKL5基因的致病变异可导致CDKL5缺乏症(CDKL5，MIM 300672,105830)，是一种严重的发育性和癫痫性脑病，与认知和运动功能障碍以及皮质视觉障碍相关。最近的数据表明，CDD是导致DeE的最常见的遗传原因之一。在CDD动物模型中的研究已经证明了改变疾病和逆转症状的能力：目前全世界正在努力开发治疗策略(包括基因疗法)来治疗并有可能治愈CDD。虽然有四项活跃的临床试验，但没有一项评估这种DeE的全谱，以解决真正的疾病修改。虽然疾病修改疗法的能力正在加速，但临床试验准备工作存在一个关键障碍，可能导致这些疗法失败，不是因为缺乏疗效，而是因为缺乏有效的结果衡量标准。CDD在历史上与Rett综合征有关，但有许多明显的区别，CDD已成为一种独立的疾病。一些临床结果测量(COMS)可以借鉴Rett综合征COMS，而另一些则需要专门为CDD开发。我们的研究网络在开发和验证结果指标方面的卓越经验与CDD专家和临床试验专家的广泛网络相结合，在为CDD开发临床试验准备方面处于独特的地位。我们的目标是1)改进和验证适当的定量COMS和生物标记物，以及2)进行多地点临床试验准备研究，以确保它们能够成功实施。我们将测试这一假设，即CDD特定的COMS可以被改进以准确和可重复性地跟踪临床试验中有意义的变化：目标1：生成和验证一套全面评估CDD疾病修改所需的COMS和生物标记物。目的2：进行一项多点临床试验准备研究，以评估实施情况、纵向稳定性，并收集基线COMS和脑电/诱发电位数据。总体影响：这些结果衡量标准将确定CDD的临床试验准备情况，并生成历史基准结果数据，确保对包括基因治疗在内的潜在新疗法进行最佳测试。此外，这些措施将适用于其他DEE，允许选择现有的NINDS支持的测量工具(NeuroQOL、PROMIS、工具箱)以外的结果测量，这些工具不是为DEE人群的严重程度设计的。

Pathogenic variants in the Cyclin-dependent kinase like 5 (CDKL5) gene cause CDKL5 deficiency disorder (CDD, MIM 300672, 105830) a severe developmental and epileptic encephalopathy (DEE) associated with cognitive and motor dysfunction and cortical visual impairment. Recent data suggest CDD is one of the most common genetic causes of DEE. Work in CDD animal models has demonstrated the ability for disease modification and symptom reversal: worldwide efforts are now underway to develop therapeutic strategies (including gene therapy) to treat and potentially cure CDD. While there are four active clinical trials, none assesses the full spectrum of this DEE to address true disease modification. While capability for disease modifying therapies is accelerating, there is a critical barrier for clinical trial readiness that may result in failure of these therapies, not due to lack of efficacy but due to lack of validated outcome measures. CDD has been associated historically with Rett syndrome but there are many clear distinctions and CDD has emerged as an independent disorder. Some Clinical Outcome Measures (COMs) can be adapted from Rett syndrome COMs, whereas others need to be developed specifically for CDD. Our research network is uniquely positioned to develop clinical trial readiness for CDD by pairing exceptional experience in the development and validation of outcome measures with an extensive network of CDD experts and clinical trialists. Our goals are to 1) refine and validate appropriate quantitative COMs and biomarkers and 2) conduct a multi-site clinical trial readiness study to ensure that they can be successfully implemented. We will test the hypothesis that CDD specific COMs can be refined to accurately and reproducibly track meaningful changes in clinical trials: Aim 1: Generate and validate a suite of COMs and biomarkers necessary to comprehensively assess disease modification in CDD. Aim 2: Conduct a multi-site clinical trial readiness study to assess implementation, longitudinal stability, and collect baseline COMs and EEG/evoked potential data. Overall Impact: These outcome measures will establish clinical trial readiness for CDD and generate historic baseline outcome data, ensuring optimal testing of potential new therapeutics including gene therapy. Furthermore, these measures will be adaptable to other DEEs by enabling choices of outcome measures beyond existing NINDS supported measurement tools (NeuroQoL, PROMIS, Toolbox) that are not designed for the severity of the DEE populations.