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

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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.