SBIR-STTR Award

There are now 50+ new drugs in Phase II-III development to treat COPD - a disease affecting 13 million Americans, costing $49B and killing 120,000 each year. However, a major limitation in evaluating therapies for these chronic diseases is the lack of a sufficiently sensitive and non-invasive method for drug developers to see efficacy on timescales of days rather than months. Without such methods, expensive drug development programs fail, and promising new drugs are never put into trials. An emerging solution is hyperpolarized 129Xe MRI, which is an extraordinarily powerful marker of regional pulmonary function and therapy response. However, its availability in major pulmonary centers is currently limited. Our long-term goal is to build a business that can broadly deploy non-invasive, high-resolution hyperpolarized 129Xe MRIs as a biomarker to help accelerate evaluation of promising therapies for respiratory diseases. The objective of this application is toimprove the size, conversion efficiency, and hence the economics of the optical cell within 129Xe polarizers. The critical need is that today's hyperpolarization technology is relatively inefficient in converting laser power into spin-polarized 129Xe. Over 80% of the available laser power is not productively converted into spin polarization. Adding additional laser power and optical cell volume to overcome conversion inefficiency results in large, expensive units that must be installed in a dedicated room, with a source of compressed air, external gas cylinders, and 3-phase power in close proximity to the MRI scanner. The rationale for the proposed project is that by using a novel optical cell geometry, it will become possible to produce highly polarized129Xe in a small, compact, economical system employing modest laser power and requiring nothing unusual of the facility. By solving this critical bottleneck, we remove major limitations fr clinical trials requiring ~20 sites to be brought on line quickly and temporarily to meet recruitment targets. Thus, the proposed research is relevant to that part of the NIH Mission that pertains to improving health by developing and accelerating the application of biomedical technologies. Guided by strong preliminary data, our design approach relies on two Specific Aims: 1) Develop a standard platform for operating and testing various new optical cell designs, and 2) Develop enhanced optical cell geometry by optimizing photon efficiency. Completion of these aims will: a) deliver a fundamentally new and improved approach to efficient optical pumping in 129Xe polarizers, b) directly measure the key performance characteristics of this new design to maximize polarization levels and throughput, and c) develop the integrated control and monitoring package needed to commercialize such a product. The proposed approach is innovative because it takes a fundamentally new approach to optical cell design that will reduce the size and facility footprint of hyperpolarization technology while improving it performance. The proposed research is significant because realization of such technology will greatly accelerate the deployment of hyperpolarized 129Xe as a biomarker in clinical trials for chronic lung disease therapies.

Thesaurus Terms:
Absorption;Affect;Air;Alkalies;American;Asthma;Base;Behavior;Bioimaging;Biological Factors;Biological Markers;Biomedical Technology;Businesses;Cell Volumes;Cells;Characteristics;Chronic;Chronic Disease;Chronic Lung Disease;Chronic Obstructive Airway Disease;Clinical;Clinical Trials;Cost;Cost Savings;Cystic Fibrosis;Data;Deposition;Design;Development;Diagnosis;Disease;Drug Development;Drug Efficacy;Drug Industry;Economics;Efficacy Testing;Elements;Equipment;Evaluation;Experience;Foundations;Gases;Geometry;Goals;Health;Heating;Hospitals;Imaging Technology;Improved;Innovation;Intellectual Property;Interstitial Lung Diseases;Intravenous Injection;Ionizing Radiation;Killings;Lasers;Logistics;Lung;Lung Diseases;Lung Imaging;Magnetic Resonance Imaging;Maintenance;Measures;Meetings;Methods;Mission;Modality;Monitor;Novel;Novel Strategies;Operation;Optics;Outcome;Patient Recruitments;Performance;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Photons;Prevent;Process;Production;Programs;Public Health Medicine (Field);Public Health Relevance;Pulmonary Function;Pump;Radioactive;Research;Research Institute;Resolution;Respiratory;Respiratory Disease/Disorder Therapy;Respiratory Physiology;Response;Services;Site;Small Business Innovation Research Grant;Solutions;Source;System;Technology;Testing;Therapeutic Clinical Trial;Treatment Response;United States National Institutes Of Health;Work;

Chronic respiratory diseases, such as COPD, asthma, and cystic fibrosis (CF), are the 3rd leading cause of death in the US, with costs exceeding $150B/year. A 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 use. Though ubiquitous, pulmonary function testing via spirometry is highly variable and insensitive to early and regional disease; bronchoscopy is insensitive to regional disease and invasive. While chest CT is sensitive to regional abnormalities, it provides little functional information, and radiation exposure limits its long- term and repeated use, particularly in children. An emerging solution to this pressing need is hyperpolarized (HP) 129Xe MRI, which provides quantitative markers of regional lung function. Currently, this technology is available only in larger research centers, primarily because it is regulated as a drug/device combination. Our long-term goal is to build a business that broadly deploys non-invasive, high-resolution HP 129Xe MRI to accel- erate treatment discovery and personalized care for lung diseases. The objective of this application is to estab- lish a marketable 129Xe hyperpolarizer and perform pediatric testing required by FDA for HP 129Xe approval and dissemination. To accomplish this objective, we will: 1) demonstrate the superior sensitivity of HP 129Xe MRI to conventional spirometry; 2) document human factors/usability studies and polarizer design under FDA-device control guidelines; and 3) demonstrate safety and utility in pediatric subjects, specifically CF patients. The ra- tionale for the project is that unlike other common chronic lung diseases, which have poorly understood dis- ease etiology and display variable disease trajectories and long time-courses, CF lung disease is caused by mutations in a single gene and displays predictable and rapid progression in adolescent CF patients, providing an ideal means to test HP 129Xe MRI against spirometry. Guided by our Phase I SBIR successes and strong preliminary data, we will accomplish these goals through three Specific Aims: 1) commission and operationally qualify a compact 129Xe hyperpolarizer; 2) demonstrate superior ability of HP 129Xe ventilation MRI to quantify 1-year lung function decline in adolescent CF patients, compared to spirometry; and 3) determine the contribu- tion of permanent airway remodeling to ventilation abnormalities. The proposed approach is innovative, be- cause it leverages improved polarization technology and end-user experience to obtain FDA mandated human factors data, meets FDA requirements for pediatric testing, and capitalizes on well-characterized decline in ad- olescent CF lung function. The proposed research is significant, because it will enable HP 129Xe technology that is easily disseminated, installed, and operated to be marketed to guide therapy development and patient treatment in all chronic lung diseases. Further, the proposed research has direct translational implications, be- cause it will provide much needed structure/function data to inform personalized care for pediatric CF patients.

Public Health Relevance Statement:
PROJECT NARRATIVE The proposed research is relevant to public health, because it advances the use of non-invasive, radiation-free imaging to diagnose and monitor lung diseases. Although the work focuses pediatric cystic fibrosis, it acceler- ates the use of this technology to evaluate novel therapies in clinical trials and measure treatment efficacy in patients with a range of diseases, including asthma and COPD. Thus, the research is relevant to the part of the NIH's mission that pertains to applying knowledge to enhance health, lengthen life, and reduce illness.

Project Terms:
Address; Adolescent; Adult; Affect; aged; airway remodeling; Asthma; base; Biological Markers; Bronchoscopy; Businesses; Cause of Death; Cessation of life; chest computed tomography; Child; Childhood; children with cystic fibrosis; Chronic; Chronic lung disease; Chronic Obstructive Airway Disease; Clinical; clinical care; Clinical Medicine; Clinical Trials; clinically relevant; Collaborations; Control Groups; cost; Cystic Fibrosis; cystic fibrosis patients; Data; design; Development Plans; Device Approval; Device Safety; Devices; Diagnosis; Diagnostic; Disease; Disease Progression; drug development; Early Intervention; Enhancement Technology; Environmental air flow; Etiology; Exhibits; experience; functional decline; Genes; Goals; Gold; Guidelines; Health; healthy volunteer; Human; Image; imaging agent; Impairment; improved; innovation; Intravenous; Ionizing radiation; Knowledge; Life; Logistics; Lung; lung development; Lung diseases; lung imaging; Magnetic Resonance Imaging; Measures; Medical center; Mission; Modeling; Monitor; Mutation; novel therapeutics; Obstruction; operation; Outcome; Partner in relationship; Patient Care; Patients; Pediatric Hospitals; Performance; personalized care; Pharmaceutical Preparations; Phase; phase III trial; Positioning Attribute; prevent; Production; Program Development; Public Health; Pulmonary Cystic Fibrosis; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary function tests; Radiation; Radiation exposure; Radioactive; Regional Disease; Research; Resolution; Respiratory physiology; response; Safety; Secure; Small Business Innovation Research Grant; Spirometry; Structure; success; System; Technology; Testing; therapy development; Time; tool; Treatment Efficacy; treatment response; United States National Institutes of Health; usability; Work