Use of donor-derived cell-free DNA for risk stratification and post-treatment monitoring of lung transplant patients at risk for chronic lung allograft dysfunction

This is an application for the K22 NHLBI Career Transition Award for Dr. Michael Keller, M.D. Dr. Keller has shown great promise as a young investigator, and has experience in conducting translational and observational research in lung transplantation. However, he is now proposing to acquire advanced training in conducting longitudinal analysis and comparative effectiveness research in lung transplant and requires additional training and mentorship to do so. His long- term goal is to develop an independent research career as a physician-scientist conducting translational and comparative effectiveness research focused on the development of interventions to prevent and treat chronic lung allograft dysfunction (CLAD) in lung transplant patients. This award will provide Dr. Keller with the support and training to accomplish this goal. He has assembled an experienced mentorship team including: Dr. Sean Agbor-Enoh (Primary Mentor, Lung Transplantation), Dr. Hannah Valantine (Translational Research and Clinical Trials) and Dr. Dean Follmann (Biostatistics). Through a combination of close mentorship, formal coursework and practical experience, Dr. Keller proposes to accomplish the following training objectives: 1) acquire advanced skills in longitudinal analysis 2) acquire skills in translational research, with a focus on clinical interventions and 3) acquire advanced skills in the design and analysis of randomized controlled trials and prospective cohort studies. Compared to other solid organ transplantation, lung-transplant patients have the lowest long-term survival, with a median survival of 6.5 years. The leading cause of mortality after the first-year of lung transplant is CLAD, an irreversible and progressive form of allograft failure that develops in about 50% of recipients by 5 years after transplantation. Given that no reliable treatment options currently exist for CLAD, emphasis is placed on identifying and addressing recognized risk factors, primarily acute lung allograft dysfunction (ALAD), in an effort to prevent disease onset. However, not all patients who experience ALAD will progress to CLAD and identifying at-risk individuals is challenging with existing clinical tools. Evidence suggests that donor-derived cell-free DNA, a molecular biomarker of lung allograft injury, may provide a more sensitive and quantitative measure of the degree of lung allograft injury than traditional clinical tools, and better define patients at risk for the development or progression of CLAD. The overall objective for this K22 application is to identify emergent relationships between plasma dd-cfDNA levels of lung transplant patients at risk for CLAD and CLAD- associated death. Dr. Keller proposes to accomplish this by pursuing three specific aims: 1) Identify key trends in plasma dd-cfDNA levels prior to and at the time of diagnosis of ALAD that predict the risk of developing CLAD; 2) Define the impact of cumulative allograft injury, as measured by dd-cfDNA, on CLAD severity and post-CLAD survival; and 3) conduct a prospective cohort study to assess the correlation between post-ALAD treatment allograft injury kinetics, assessed by dd-cfDNA, and risk of developing CLAD. The proposed research is innovative, in the applicant’s opinion, because it represents a substantive departure from the status quo by evaluating allograft injury at the molecular level to guide risk stratification, post-transplant monitoring and treatment response in lung transplant recipients. These contributions will be significant because they are expected to provide strong scientific justification for the development of future clinical studies aimed at the prevention and treatment of patients at heightened risk for CLAD and CLAD progression, as well as trials evaluating the effectiveness of dd-cfDNA-based treatment goals in the treatment of ALAD. Ultimately, such knowledge has the potential to offer new opportunities for the development of innovative monitoring and treat Project Number: 1K22HL166368-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Michael Keller | Institution: UNIVERSITY OF MARYLAND BALTIMORE, BALTIMORE, MD | Award Amount: $248,999 | Activity Code: K22 | Study Section: NHLBI Mentored Transition to Independence Study Section[MTI (OA)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K22HL16636801