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

PHOX2B 先天性中枢性通气不足综合征 (CCHS) 的生理特征为未来的临床试验做好准备

• 批准号: 10514295
• 负责人: DEBRA ELLYN WEESE-MAYER
• 金额: $ 7.75万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10514295
• 关键词: Admission activity; Anesthetics; Autonomic nervous system; Biological Markers; Biotechnology; Breathing; Cardiovascular system; Caring; Case Study; Cell model; Clinical; Clinical Trials; Complex; Conduct Clinical Trials; Congenital Megacolon; Data; Data Analytics; Data Set; Development; Device Approval; Devices; Disease; Disease Marker; Disease Progression; Drug Approval; Drug usage; Echocardiography; Future; Genes; Geography; Gold; Health; Home; Hospitals; Hour; Hypoventilation; Hypoxia; Impairment; Individual; Inpatients; Intervention; Laboratories; Life; Measures; Medical Records; Medical center; Molecular; Morbidity - disease rate; Mutation; Neural Crest; Neurocognitive; Neuroepithelial, Perineurial, and Schwann Cell Neoplasm; Newborn Infant; Online Mendelian Inheritance In Man; Outcome; Outcome Assessment; Oxygen; Participant; Pathogenicity; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phenotype; Physiological; Population; Precipitating Factors; Precipitation; Process; Property; Psychometrics; Rare Diseases; Readiness; Reporting; Resources; Respiratory Tract Infections; Rest; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Time; Time Study; Training; Travel; biomarker validation; biomedical referral center; burden of illness; cerebrovascular; clinical outcome assessment; cohort; comorbidity; congenital central hypoventilation syndrome; cost; design; digital; empowered; experience; high risk; insight; mortality; neurocognitive test; off-label drug; palliative; potential biomarker; respiratory; success; therapeutic candidate; ventilation

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.

项目摘要 先天中央中央低文化综合征（CCHS）（OMIM＃209880），这是一种罕见而严重的神经疾病 通常在新生儿时期出现，其特征是深度不足和自动障碍。 控制呼吸，必要的终生人工通风。神经认知结果常常受到损害 至少部分是由于重复性低氧和高碳水化合物暴露的影响。患者患有频谱 与自主性失调兼容的严重症状。目前，没有药物结肠干预措施 被证明可以减少CCH中的疾病伯嫩，并且可用的有限治疗选择高度 侵入性，朴素，只提供姑息支持。长期以来认为是一种先天性疾病，对 长期改善，越来越多的证据表明，CCHS表型的许多方面是 随着时间的流逝而发展且对干预敏感的持续疾病过程。最近的CCHS案件有 据报道，直到降水因素（例如呼吸道感染或麻醉）才出现正常 接触。这些病例表明，至少一些CCHS患者保持生理潜力 没有人工通风，并希望可以逆转CCH的某些严重方面。潜力 在CCHS病例报告中成功使用标签非标签药物的报道强调了治疗性干预措施， 细胞模型，表明可能逆转与CCHS相关的致病过程，发展和 批准在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 疾病稳定性和进展的标准评估需要住院和专业测试 在只有少数具有CCHS专业知识的推荐中心之一。考虑到稀有性和地理分散 CCHS患者，这限制了临床试验评估潜在治疗的潜力。几十年来 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，年度 测试，包括实验室，72小时的录音，全面的生理学内4天和4晚 录音和神经认知测试> 85例患者和> 350次入院，代表世界 最大的CCHS队列具有有关疾病进展的纵向数据。利用这个队列，我们​​已经确定了 反映核心CCHS表型的几种潜在的生物标志物和临床结果评估（COA） 并且可以在当地医院或CCHS患者的家中进行远程测量 需要前往CCHS推荐中心。使用此R03应用程序，我们建议利用此单数数据 设置通过建立重新测试来验证这些生物标志物和COA的心理测量特性 与金标准评估相比，可靠性，灵敏度，纵向稳定性和临床有效性。 总体目的是赋予对临床试验的设计，进行和解释，以评估候选治疗， 增加他们成功的可能性。最新证据表明有多种干预措施使这项研究 时间敏感及其成功至关重要，允许进步降低CCHS患者的发病率和死亡率。