Cell Based Immunomodulation to Promote Post-Infarct Myocardial Repair

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PROJECT SUMMARY Ischemic heart disease is the leading cause of death in the industrialized world. Heart failure (HF) develops in 20-30% of patients after myocardial infarction (MI) due to extensive scarring exacerbated by a persistent 2.9- fold increase of inflammatory macrophages in the infarct borderzone and remote myocardium. Cytokines, such as Interleukin-10 (IL-10), and cytokine inhibitors, such as Interleukin-1 receptor antagonists (IL-1Ra), are potent immune modulators that regulate inflammation, reduce infarct size, and improve ventricular function. However, translation of cytokine therapy to patients has been limited by poor biodistribution, toxicity, and paradoxical pro- inflammatory responses with sustained administration. Local immunomodulation with cell therapy secretion of cytokines holds promise, but poor cell survival (<1%) and reduced in vivo potency have remained critical barriers preventing clinical translation. We have overcome these critical limitations by developing an innovative and translational cell therapy platform that enables sustained locally administration to the heart after MI. We have engineered retinal pigment epithelial (RPE) cells to produce IL-1Ra and IL-10 in a more physiologically relevant paracrine fashion at high local concentrations without systemic absorption and have encapsulated them in alginate-based core-shell capsules, shielding them from the host immune system and allowing them to serve as a regulatable in situ cytokine “factories”. We have demonstrated that local delivery modulates inflammation and improves outcomes after acute MI. In this proposal, we hypothesize that epicardial implantation of RPE-IL10 and RPE-IL1Ra will sustain reductions in post-MI chronic inflammation and reverse cardiomyopathic remodeling in HF. In Aim 1, RPE cell capsule systems will be developed and optimized for sustained 6 month secretion of IL- 10 and IL-1Ra with integration of an apoptotic cell safety switch to cease therapy post-administration. In Aim 2, these IL-10 and IL-1Ra cytokine factories will be validated as mono- or combination therapies in a chronic post- MI rat HF model by confirming reduction of the cardiac inflammasome, promotion of reparative macrophage phenotypes, and reversal of adverse cardiac remodeling. In Aim 3, the ability to titrate and cease therapy post- implantation in a clinically relevant fashion will be evaluated in a porcine model. Efficacy of RPE therapy will be tested in a chronic porcine infarct model over 100 days. The proposed work is expected to result in a new immune modulatory strategy for MI and elucidate mechanisms of cytokine therapy on the cardiac inflammasome. Importantly, the developed biotechnology will be ready for pre-clinical testing and has translational benefit beyond cytokines alone, as it can be utilized for a wide range of protein and local drug delivery directly to the heart.