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

项目摘要 先天性中枢性通气不足综合征（CCHS）（OMIM #209880），一种罕见的重度神经嵴病 典型地出现在新生儿时期，特征为严重的换气不足和自动呼吸功能受损 控制呼吸，需要终身人工通气。神经认知结果往往受到损害 至少部分是由于反复低氧和高碳水化合物暴露的影响。患者患有一系列 与自主神经失调相符的严重症状目前，没有任何药物干预措施 已被证明可以减少CCHS的疾病负担，并且有限的治疗选择非常困难。 侵入性、负担沉重且仅提供治标不治本的支持。长期以来被认为是一种先天性疾病， 长期改善，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 据报道，在出现沉淀因素（如呼吸道感染或麻醉剂）之前， exposure.这些病例表明，至少有一些CCHS患者保持了生理功能 没有人工通气，并提供了希望，一些严重的方面CCHS可以扭转。潜力 CCHS病例报告中成功的标签外药物使用报告强调了治疗干预， 细胞模型表明逆转CCHS相关致病过程的潜力， 在其他疾病人群中批准具有改变CCHS游戏规则潜力的器械。目前，黄金- 疾病稳定性和进展的标准评估需要住院和专门的测试 在少数几个拥有社区卫生服务专业知识的转诊中心之一。由于稀有和地理分散， 对于CCHS患者，这限制了临床试验评估潜在治疗方法的可能性。几十年来， 为CCHS患者提供护理，我们开发了一个数据集，包括详细的医疗记录，年度 测试包括实验室工作、72小时霍尔特记录、实验室内4天4夜的综合生理学 记录和神经认知测试的一个队列的>85例患者和>350入院，代表了世界上 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表型的几种潜在生物标志物和临床结局评估（COA） 可以在当地医院或CCHS患者家中进行远程测量， 需要前往CCHS转诊中心。在此R 03应用程序中，我们建议利用此奇异数据 通过建立这些生物标志物和COA的休息-重测， 可靠性、灵敏度、纵向稳定性和临床有效性。的 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， 增加他们成功的可能性。最近的证据表明，几种干预措施的潜力，使这项研究 时间敏感，其成功对于降低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.