Friday, May 9, 2025
5/9/2025
Phenotyping Net Immune State with MicroRNAs in Cardiac Transplantation - Currently, there are no reliable clinical strategies available to optimize immunosuppression levels after heart transplantation. Patient survival after heart transplant is limited to 12 years and has not improved in the past two decades largely attributed to the side effects of immunosuppression. Immunosuppression is used to prevent heart transplant rejection, but the protective effects of immunosuppression are offset by multiple complications including infection, chronic kidney disease, and cancer. There is no available biomarker available to assess the alloimmune response after transplant and guide titration of immunosuppression. Thus, contemporary clinical practice is to wean immunosuppression when drug toxicity arises or based on time after transplant. Through circulating microRNAs, small non-coding RNA molecules, we will predict complications of over- (infection) and under-immunosuppression (rejection). We hypothesize that circulating microRNAs can be used to quantify the net immune state of heart transplant patients and identify patients at high risk for immunosuppression-related complications. The scientific aims of this study will be accomplished through serial blood-based microRNA sequencing and deep clinical phenotyping. We will build on our strong preliminary data to develop a panel of microRNAs that predict these key post-transplant complications and correlate with varying doses or levels of contemporary immunosuppression. This work will form the basis for a non-invasive, genomic blood test that can be used to monitor patients after heart transplant to mitigate complications and enhance long-term survival. The scientific aims of this proposal will be achieved through a prospective, multicenter, multiracial cohort study of adult heart transplant patients (n=250) enrolled at 8 geographically- and socioeconomically diverse transplant centers, with a high proportion of Black patients (target enrollment 30%) as these patients have worse clinical outcomes after transplant. The specific aims of this proposal are: 1) identify circulating microRNAs that predict the risk of major over- and under-immunosuppression related adverse events after heart transplantation, 2) determine the response of the circulating microRNA transcriptome in heart transplant patients to changes in immunosuppressive therapy, and 3) develop and validate a clinical microRNA score that provides a quantitative assessment of the patient’s net immune state. This study will address several critical barriers needed to reduce complications of immunosuppression, enhance patient quality of life, and improve long-term survival. Development and validation of this microRNA biomarker panel in this study forms the basis for a new blood test that can be used to manage transplant patients. This would allow clinicians to balance the risks of over- and under-immunosuppression to personalize medications after heart transplant. The patient-specific assessment of net immune state can then be evaluated in future randomized, controlled, clinical trials, where the microRNA panel informs the titration of immunosuppression with the goal of mitigating the adverse event rate and enhancing patient survival. This research also has important implications for other solid organ transplant populations.
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