Anthracycline (e.g. doxorubicin) induced cardiomyopathy (AIC) is a condition in which anthracycline toxicity leads to impaired myocardial function by causing direct myocardial toxicity. Anthracyclines are routinely used to treat breast cancer, lymphoma, and leukemia and carry a 7.8-8.8% risk of causing cardiomyopathy. Though therapies such as beta-blockers and angiotensin-converting enzyme inhibitors can offer significant myocardial protection, AIC is associated with a 3.5 times greater relative risk of death than ischemic or idiopathic cardiomyopathy. New therapies are desperately needed and stem cell based technologies offer a novel approach to myocardial protection and repair. This document proposes a study evaluating the use of mesenchymal stem cells (MSCs) to preserve viability and function in AIC patient-specific induced cardiomyocytes (iCMs) after exposure to doxorubicin. For this study I am recruiting five AIC patients.
Aim 1 will be to adapt an innovative iCM platform to predict the efficacy of mesenchymal stem cells (MSCs) in treating AIC. To test this, MSCs will be co-cultured with AIC patient-specific ICMs in the presence of doxorubicin. iCM function and viability will then be rigorously assessed.
Aim 2 will be to elucidate the mechanisms by which MSCs preserve myocardial viability and function after exposure to doxorubicin. To test this we will isolate exosomes from MSC culture and compare their ability to preserve AIC patient-specific iCM viability and function after exposure to doxorubicin to that of MSCs in co- culture. Lastly, I will sequence exosomal miRNAs to identify the specific mechanisms of endogenous repair utilized by MSCs and exosomes. This proposed study will improve our understanding of the role of MSCs in treating AIC and could potentially open doors for the development of much needed novel therapies for AIC.
Anthracycline induced cardiomyopathy (AIC) one of the most deadly forms of cardiomyopathy. Even with optimal medical therapy, mortality rates in excess of 20% at four years have been reported. For patients with severe cases, the only options available are cardiac transplantation or implantation of a left ventricular assist device. Novel therapies are needed, and mesenchymal stem cells have emerged as a promising method by which to activate endogenous myocardial repair pathways leading to improved myocardial viability and function. Thus, I propose a study evaluating mesenchymal stem cells as a novel therapy for AIC.
