PHOX2B Congenital Central Hypoventilation Syndrome (CCHS) Physiologic Signatures in Readiness for Future Clinical Trials

项目摘要 先天性中枢性低通气综合征(OMIM#209880)--一种罕见而严重的神经危象 典型的表现在新生儿期，特征是严重的换气不足和自主性受损 控制呼吸，需要终生人工呼吸机。神经认知结果通常会受到损害 至少部分是由于反复低氧和高碳水化合物暴露的影响。患者患有一种谱系 与自主神经失调相适应的严重症状。目前，还没有药物干预措施 已经证明可以减轻CCHS的疾病负担，可用的有限的治疗选择非常有限 侵犯性的，繁重的，只提供姑息的支持。长期以来被认为是一种先天性疾病，希望渺茫 长期的改善，越来越多的证据表明，CCHS表型的许多方面是 随着时间的推移而发展并对干预敏感的持续疾病过程。最近的CCHS病例有 据报道，在出现沉淀因素(如呼吸道感染或麻醉剂)之前，他们看起来正常 曝光。这些病例表明，至少有一些CCHS患者保持了生理潜力以发挥作用。 没有人工通风，并提供了希望，CCHS的一些严重方面可以扭转。潜在的 CCHS病例报告中成功使用标签外药物的报告强调了治疗干预， 细胞模型显示有可能逆转CCHS相关的致病过程，以及发育和 批准CCHS中具有改变游戏规则潜力的其他疾病人群中的设备。目前，黄金- 对疾病稳定性和进展的标准评估需要住院和专门的测试 在为数不多的几个拥有CCHS专业知识的转介中心之一。鉴于稀有性和地理上的分散性 对于CCHS患者，这限制了临床试验评估潜在疗法的潜力。在几十年的时间里 为CCHS患者提供护理，我们开发了一个数据集，其中包括详细的医疗记录，每年 测试包括实验室工作、72小时动态心电记录、实验室内4天4夜的全面生理记录 为85名患者和350名入院患者进行的录音和神经认知测试，代表着世界上 具有疾病进展纵向数据的最大CCHS队列。利用这个队列，我们已经确定了 反映核心CCHS表型的几个潜在生物标志物和临床结果评估(COA) 可以在当地医院或CCHS患者家中远程测量，而不需要 需要到CCHS转诊中心出差。对于此R03应用程序，我们建议利用此单一数据 通过建立休息-重测来验证这些生物标记物和COA的心理测量特性 与黄金标准评估相比，可靠性、敏感性、纵向稳定性和临床有效性。这个 总体目标是授权临床试验的设计、实施和解释，以评估候选疗法， 增加了他们成功的可能性。最近有证据表明可能会有几种干预措施，这项研究 时间敏感性及其成功对于推动降低CCHS患者的发病率和死亡率至关重要。

Project Abstract Congenital central hypoventilation syndrome (CCHS)(OMIM #209880), a rare and severe neurocristopathy typically presenting in the newborn period and characterized by profound hypoventilation and impaired automatic control of breathing, necessitates life-long artificial ventilation. Neurocognitive outcome is often compromised due at least in part to the impact of repetitive hypoxic and hypercarbic exposure. Patients suffer from a spectrum of severe symptoms compatible with autonomic dysregulation. Currently, no pharmacologic interventions have been demonstrated to decrease disease burden in CCHS, and the limited treatment options available are highly invasive, burdensome and offer only palliative support. Long considered a congenital disease with little hope for long-term improvement, mounting evidence suggests that many aspects of the CCHS phenotype are part of ongoing disease processes that develop over time and are sensitive to intervention. Recent CCHS cases have been reported who appeared normal until a precipitation factor, such as respiratory infection or anesthetic exposure. These cases indicate that at least some CCHS patients maintain the physiologic potential to function without artificial ventilation and offer hope that some severe aspects of CCHS could be reversed. Potential for therapeutic intervention has been highlighted by reports of successful off-label drug use in CCHS case reports, cellular models indicating potential for reversing CCHS-related pathogenic processes, and development and approval of devices in other disease populations that have game-changing potential in CCHS. Currently, gold- standard assessment of disease stability and progression requires inpatient admission and specialized testing at one of only a handful of referral centers with CCHS expertise. Given the rarity and geographic dispersion of CCHS patients, this limits potential for clinical trials to assess potential therapeutics. Over several decades of providing care to CCHS patients, we have developed a data set that includes detailed medical records, annual testing including labwork, 72-hour Holter recordings, comprehensive physiologic in-laboratory 4-day and 4-night recordings, and neurocognitive testing for a cohort of >85 patients and >350 admissions, representing the world’s largest CCHS cohort with longitudinal data on disease progression. Utilizing this cohort, we have identified several potential biomarkers and clinical outcome assessments (COAs) that reflect the core CCHS phenotype and could be measured remotely, in the local hospital setting or in the homes of CCHS patients, without need for travel to a CCHS referral center. With this R03 application we propose to leverage this singular data set to validate the psychometric properties of these biomarkers and COAs by establishing their rest-retest reliability, sensitivity, longitudinal stability and clinical validity as compared to gold-standard assessments. The overall aim is to empower design, conduct, and interpretation of clinical trials to assess candidate therapeutics, increasing their likelihood of success. Recent evidence of the potential for several interventions make this study time-sensitive and its success paramount to allow advances to reduce morbidity and mortality in CCHS patients.