Lung transplantation is the last treatment option for patients with end-stage lung diseases and to improve life expectancy and quality. While current technology has significantly improved the short-term survival rates, long- term survival remains a challenge due to chronic lung rejection, attributed to the development of Bronchiolitis Obliterans Syndrome (BOS), an irreversible and progressive decrease in lung function. Besides lung transplant, BOS is also a severe complication for patients receiving allogeneic hematopoietic cell transplant. Currently, diagnosis of BOS relies on the substantial and progressive reduction of lung function as measured by spirometry, but such a diagnosis would be too late for most treatments in order to slow down the deterioration of lung function. Recently, several biomarkers, including endothelin-1 (ET-1), sCD30, and KL-6, have been identified as predictive markers for BOS, making early warning possible. However, current methods for detecting these biomarkers are either cumbersome or expensive for point-of-care (POC) settings. To overcome these technological barriers in order to achieve the goal of providing early warning for BOS, we propose to develop a user-friendly device for POC monitoring for levels of ET-1, sCD30 and KL-6 based on the existing blood glucose meter (BGM) technology. By converting and amplifying the binding of non-glucose targets to their antibodies to release an enzyme called invertase, which catalyzes the conversion of sucrose to glucose, concentrations of these markers can be correlated to glucose, which can then be directly measured by a BGM. Specifically, based on the method developed for the ET-1 assay, we will first demonstrate the chemistry to obtain the critical invertaseâsCD40 and âKL6 conjugates, followed by assay development, optimizations, and last to integrate the optimized assays with an existing prototype cartridge system. Unlike current assays that rely on delicate instrument with highly trained operators, our proposed system is simple and inexpensive to be used at the POC settings. In addition, the biomarker tests will be utilize the same platform GlucoSentient has developed for tacrolimus, an immunosuppressant widely used by transplant patients and requires close monitoring. Todayâs BGM is the culmination of decades of research and development, designed for convenient operation, low cost and large-scale production. Leveraging the BGM technology allows us to reduce the risks and costs associated with device development and scale up production. By combining the gold standard of antibody-based assays with the low cost and easy-to-use BGM technology, we aim to develop a single product that allows post- transplant patients and their doctors to monitor the risk of developing BOS and immunosuppressant levels. The proposed assays for BOS markers, alongside a recently developed assay to monitor tacrolimus, the most common immunosuppressant for lung transplant, has great potential to benefit both the physicians and patients to prevent chronic lung rejection and to improve long-term patient outcome.
Public Health Relevance Statement: Project Narrative Building on existing low-cost blood glucose meter hardware, GlucoSentient proposes to develop point-of- care tests for the quantification of endothelin-1, soluble CD30 and KL-6, serum markers for early warning of Bronchiolitis Obliterans Syndrome, which is the major limiting factor for the long term survival of lung transplant patients, as well as hematopoietic cell transplant patients. Early detection of BOS can lead to more effective therapies aimed at stabilizing the disease, which is important as the effects of BOS are currently irreversible by existing treatments. Providing patients as well as physicians with a low-cost, easy-to-use, and accurate prognostic tests for BOS can improve lung transplant patientsâ life expectancy, quality of life, and decrease healthcare costs.
Project Terms: Algorithms; Allogenic; Antibodies; assay development; base; Bedside Testings; Binding; Biological Assay; Biological Markers; Blood Glucose; Bronchiolitis Obliterans; Buffers; Caregivers; Caring; Cause of Death; Cell Transplants; Chemistry; Chronic; Cicatrix; Clinical; clinical application; clinical Diagnosis; clinical efficacy; Collaborations; Communities; Complication; cost; Data; design; Detection; Deterioration; Development; Device or Instrument Development; Devices; Diagnosis; Disease; Disease Management; Disease Progression; dosage; Drug Monitoring; Early Diagnosis; effective therapy; Electronic Health Record; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Enzymes; Exhalation; Foundations; functional improvement; Glucose; glucose monitor; Goals; Gold; Health Care Costs; health management; Hematopoietic; Home environment; Human; Immunoassay; Immunosuppressive Agents; improved; Industrialization; innovation; instrument; Invertase; large scale production; Lead; Life Expectancy; loss of function; Lung; Lung diseases; Lung Transplantation; Measures; Methods; Monitor; operation; Operative Surgical Procedures; Organ Transplantation; Outcome; outcome forecast; Patient-Focused Outcomes; Patients; Performance; Pharmaceutical Preparations; Phase; phase 2 study; Physicians; point of care; predictive marker; prevent; Procedures; Production; prognostic assays; prototype; pulmonary function; Quality of life; Research; research and development; research clinical testing; Respiratory physiology; Risk; Route; scale up; Serum; Serum Markers; Small Business Innovation Research Grant; Solid; Spirometry; Sucrose; Survival Rate; Syndrome; System; Tacrolimus; Techniques; Technology; Test Result; Testing; Therapeutic; Time; Tissues; TNFRSF8 gene; Training; transmission process; Transplant Recipients; Transplantation; user-friendly; Validation; validation studies; Vision; Wireless Tec
