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 （CDKL5）基因的致病变异导致CDKL5缺乏性障碍（CDD, MIM 300672, 105830），一种严重的发育性和癫痫性脑病（DEE），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DEE最常见的遗传原因之一。在CDD动物模型上的工作已经证明了疾病改变和症状逆转的能力：全世界正在努力制定治疗策略（包括基因治疗）来治疗和可能治愈CDD。虽然目前有四项正在进行的临床试验，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发展，但临床试验准备方面存在一个关键障碍，可能导致这些疗法的失败，不是由于缺乏疗效，而是由于缺乏经过验证的结果测量。CDD历来与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）可以适用于Rett综合征的COMs，而另一些则需要专门针对CDD制定。我们的研究网络具有独特的优势，通过将CDD专家和临床试验人员组成的广泛网络，在开发和验证结果措施方面的卓越经验相结合，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COMs和生物标志物，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。我们将验证CDD特异性COMs可以精确和可重复地跟踪临床试验中有意义的变化的假设：目标1：生成并验证一套COMs和生物标志物，以全面评估CDD的疾病改变。目标2：开展一项多地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EEG/诱发电位数据。总体影响：这些结果测量将建立CDD的临床试验准备情况，并产生历史基线结果数据，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，这些措施将通过在现有的NINDS支持的测量工具（NeuroQoL， PROMIS, Toolbox）之外选择结果测量来适应其他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.