Aligned Nanofibrillar Scaffolds for Controlled Delivery of Modified mRNA.
Tissue engineering. Part A
Multicellular Interactions in 3D Engineered Myocardial Tissue.
Frontiers in cardiovascular medicine
2018; 5: 147
RNA-based vector delivery is a promising gene therapy approach. Recent advances in chemical modification of mRNA structure to form modified mRNA (mmRNA or cmRNA or modRNA) have substantially improved their stability and translational efficiency within cells. However, mmRNA conventionally delivered in solution can be taken up non-specifically or become cleared away prematurely, which markedly limits the potential benefit of mmRNA therapy. To address this limitation, we developed mmRNA-incorporated nanofibrillar scaffolds that could target spatially localized delivery and temporally controlled release of the mmRNA both in vitro and in vivo. To establish the efficacy of mmRNA therapy, mmRNA encoding reporter proteins such as green fluorescence protein (GFP) or firefly luciferase (Fluc) was loaded into aligned nanofibrillar collagen scaffolds. The mmRNA was released from mmRNA-loaded scaffolds in a transient and temporally controlled fashion and induced transfection in human fibroblasts in a dose-dependent manner. In vitro transfection was further verified using mmRNA encoding the angiogenic growth factor, hepatocyte growth factor (HGF). Finally, scaffold-based delivery of HGF mmRNA to the site of surgically induced muscle injury in mice resulted in significantly higher vascular regeneration after 14 days, compared to implantation of Fluc mmRNA-releasing scaffolds. After transfection with Fluc mmRNA-releasing scaffold in vivo, Fluc activity was detectable and localized to the muscle region, based on non-invasive bioluminescence imaging. Scaffold-based local mmRNA delivery as an off-the-shelf form of gene therapy has broad translatability for treating a broad range of diseases or injuries.
View details for PubMedID 29717619
Cardiovascular disease is a leading cause of death in the US and many countries worldwide. Current cell-based clinical trials to restore cardiomyocyte (CM) health by local delivery of cells have shown only moderate benefit in improving cardiac pumping capacity. CMs have highly organized physiological structure and interact dynamically with non-CM populations, including endothelial cells and fibroblasts. Within engineered myocardial tissue, non-CM populations play an important role in CM survival and function, in part by secreting paracrine factors and cell-cell interactions. In this review, we summarize the progress of engineering myocardial tissue with pre-formed physiological multicellular organization, and present the challenges toward clinical translation.
View details for PubMedID 30406114