A Phase III Trial to Validate HP 129Xe MRI as a Functional Pulmonary Biomarker in Pediatric Lung Disease

PROJECT SUMMARYABSTRACT Chronic respiratory diseasessuch as COPDasthmaand cystic fibrosisCFare therd leading cause of death in the USwith costs exceeding $B yearA major obstacle to evaluate therapies for these diseases is that currently available tools to assess lung function are either insensitive to early disease or unsuitable for longitudinal useThough ubiquitouspulmonary function testing via spirometry is highly variable and insensitive to early and regional diseasebronchoscopy is insensitive to regional disease and invasiveWhile chest CT is sensitive to regional abnormalitiesit provides little functional informationand radiation exposure limits its longterm and repeated useparticularly in childrenAn emerging solution to this pressing need is hyperpolarizedHPXe MRIwhich provides quantitative markers of regional lung functionCurrentlythis technology is available only in larger research centersprimarily because it is regulated as a drug device combinationOur long term goal is to build a business that broadly deploys non invasivehigh resolution HPXe MRI to accelerate treatment discovery and personalized care for lung diseasesThe objective of this application is to establish a marketableXe hyperpolarizer and perform pediatric testing required by FDA for HPXe approval and disseminationTo accomplish this objectivewe willdemonstrate the superior sensitivity of HPXe MRI to conventional spirometrydocument human factors usability studies and polarizer design under FDA device control guidelinesanddemonstrate safety and utility in pediatric subjectsspecifically CF patientsThe rationale for the project is that unlike other common chronic lung diseaseswhich have poorly understood disease etiology and display variable disease trajectories and long time coursesCF lung disease is caused by mutations in a single gene and displays predictable and rapid progression in adolescent CF patientsproviding an ideal means to test HPXe MRI against spirometryGuided by our Phase I SBIR successes and strong preliminary datawe will accomplish these goals through three Specific Aimscommission and operationally qualify a compactXe hyperpolarizerdemonstrate superior ability of HPXe ventilation MRI to quantifyyear lung function decline in adolescent CF patientscompared to spirometryanddetermine the contribution of permanent airway remodeling to ventilation abnormalitiesThe proposed approach is innovativebecause it leverages improved polarization technology and end user experience to obtain FDA mandated human factors datameets FDA requirements for pediatric testingand capitalizes on well characterized decline in adolescent CF lung functionThe proposed research is significantbecause it will enable HPXe technology that is easily disseminatedinstalledand operated to be marketed to guide therapy development and patient treatment in all chronic lung diseasesFurtherthe proposed research has direct translational implicationsbecause it will provide much needed structure function data to inform personalized care for pediatric CF patients PROJECT NARRATIVE The proposed research is relevant to public healthbecause it advances the use of non invasiveradiation free imaging to diagnose and monitor lung diseasesAlthough the work focuses pediatric cystic fibrosisit accelerates the use of this technology to evaluate novel therapies in clinical trials and measure treatment efficacy in patients with a range of diseasesincluding asthma and COPDThusthe research is relevant to the part of the NIHandapos s mission that pertains to applying knowledge to enhance healthlengthen lifeand reduce illness