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

CDKL5 缺乏症临床试验准备的生物标志物和核心临床结果指标的多中心验证

• 批准号: 10569019
• 负责人: TIMOTHY A BENKE
• 金额: $ 90.23万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569019
• 关键词: Acceleration; Address; Animal Model; Behavior; Biological Markers; CDKL5 disorder; Clinical; Clinical Research; Clinical Trials; Communication; Consensus; Cyclin-Dependent Kinases; Data; Data Reporting; Databases; Development; Disease; Electroencephalography; Ensure; Epilepsy; Equipment and supply inventories; Evoked Potentials; Family; Foundations; Future; Genes; Genetic; Goals; Hand functions; Impaired cognition; International; Interview; Knowledge; Maps; Measurement; Measures; Methods; Modification; Motor; Multi-Institutional Clinical Trial; National Institute of Neurological Disorders and Stroke; Outcome; Outcome Measure; Parents; Pathogenicity; Patients; Phenotype; Population; Positioning Attribute; Protocols documentation; Qi; Quality of life; Reporting; Reproducibility; Research; Rest; Rett Syndrome; Severities; Site; Sleep; Structure; Symptoms; Testing; Therapeutic; Training; Treatment Failure; Validation; Variant; Work; biomarker validation; clinical outcome measures; clinical trial protocol; clinical trial readiness; cortical visual impairment; disability; epileptic encephalopathies; experience; gene therapy; implementation evaluation; motor disorder; motor impairment; novel therapeutics; potential biomarker; tool

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.

细胞周期蛋白依赖性激酶（例如5（CDKL5）基因）的致病变异引起CDKL5缺乏障碍（CDD，MIM 300672，105830）一种与认知和运动障碍和皮质视觉障碍相关的严重发育和癫痫性脑病（DEE）。最近的数据表明，CDD是DEE最常见的遗传原因之一。 CDD动物模型中的工作证明了疾病修饰和症状逆转的能力：现在正在进行制定治疗策略（包括基因治疗）治疗和可能治愈CDD的努力。虽然有四项主动临床试验，但没有一个评估该DEE的完整范围来解决真正的疾病修饰。尽管修饰疗法的疾病能力正在加速，但临床试验准备就绪存在关键障碍，可能导致这些疗法失败，而不是由于缺乏疗效，而是由于缺乏验证的结果指标。 CDD历史上与Rett综合征有关，但是有许多明显的区别，CDD已成为一种独立的疾病。一些临床结局指标（COM）可以从RETT综合征COM中进行调整，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位置，可以通过将成果指标的开发和验证与CDD专家和临床试验者的广泛网络相结合，以开发CDD的临床试验准备就绪。我们的目标是1）完善并验证适当的定量COM和生物标志物以及2）进行多站点的临床试验准备工作，以确保可以成功实施它们。我们将检验以下假设：CDD特定的COM可以精确且可重复地跟踪临床试验中的有意义的变化：AIM 1：生成和验证一套COM和生物标志物，以全面评估CDD中的疾病修饰所必需的疾病。目标2：进行多站点临床试验准备研究，以评估实施，纵向稳定性并收集基线COM和EEG/诱发的潜在数据。总体影响：这些结果指标将建立CDD的临床试验准备就绪，并产生历史性的基线结果数据，从而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NIND支持测量工具（Neuroqol，Promis，Toolbox）之外的结果选择来适应其他DEE，这些措施不是为DEE种群的严重性而设计的。