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

细胞周期蛋白依赖性激酶样5（CDKL 5）基因的致病性变体导致CDKL 5缺乏症（CDD，MIM 300672，105830），这是一种与认知和运动功能障碍以及皮质视觉障碍相关的严重发育性和癫痫性脑病（DEE）。最近的数据表明，CDD是DEE最常见的遗传原因之一。在CDD动物模型中的工作已经证明了疾病修饰和症状逆转的能力：目前正在世界范围内努力开发治疗策略（包括基因治疗）来治疗和潜在地治愈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，以解决真正的疾病改变。虽然疾病修饰疗法的能力正在加速，但临床试验准备存在一个关键障碍，可能导致这些疗法失败，不是由于缺乏疗效，而是由于缺乏经验证的结局指标。 CDD在历史上与Rett综合征有关，但有许多明确的区别，CDD已成为一种独立的疾病。一些临床结局指标（COMs）可以改编自Rett综合征COMs，而另一些则需要专门针对CDD开发。我们的研究网络具有独特的优势，通过将结局指标开发和验证方面的卓越经验与广泛的CDD专家和临床试验专家网络相结合，为CDD的临床试验做好准备。我们的目标是1）完善和验证适当的定量COM和生物标志物，2）进行多中心临床试验准备研究，以确保它们可以成功实施。我们将测试这样的假设，即可以对CDD特异性COM进行改进，以准确和可重复地跟踪临床试验中有意义的变化：目的1：生成和验证一套全面评估CDD疾病改变所需的COM和生物标志物。目标二：进行多中心临床试验准备研究，以评估实施情况、纵向稳定性，并收集基线COM和EEG/诱发电位数据。总体影响：这些结果指标将建立CDD的临床试验准备状态，并生成历史基线结果数据，确保对潜在的新疗法（包括基因疗法）进行最佳测试。此外，这些指标将通过选择现有NINDS支持的测量工具（NeuroQoL、PROMIS、EQUIPMENT）之外的结局指标而适用于其他DEE，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.