Endothelial inflammation is now appreciated to be a significant contributing factor in many forms of cardiovascular disease and has become the focal point of many developing therapies. Several microRNAs (miRNAs) have been identified as playing key regulatory roles in the response of human endothelium to pro- inflammatory cues, suggesting that anti-sense therapies designed to inhibit the activity of these miRNAs may be a viable therapeutic approach. Indeed, recent studies in animal models have demonstrated proof of principle that inhibition of pro-inflammatory miRNAs, such as miR-92a, can be an effective strategy for resolving endothelial inflammation. In spite of the promise these studies provide, there exist major impediments to the translation of anti-miRNA agents from animal models to therapies capable of reversing chronic inflammation in human cardiovascular disease. Most notably, the pharmacokinetic properties and biodistribution of systemically administered anti-miRNA agents are quite poor. One solution to these issues is packaging the anti- miRNA molecules within nanoscale delivery vehicles that are capable of ensuring that the drugs are routed to and maintained within the inflamed vasculature. In this proposal we aim to develop a polymeric nanoparticle delivery platform capable of delivering sustained levels of a peptide-nucleic-acid based anti-miR-92a agent. The nanoparticles will be molecularly targeted to sites of inflammation via conjugation of antibodies to E- selectin, an adhesion molecule upregulated on certain inflamed endothelium. In order to help bridge the gap from animal models to a realized human therapy, we will employ humanized mice models allowing us to target and treat inflamed human vasculature within an in vivo setting. If successful, these experiments will hasten the development of safe and effective anti-miRNA therapies for resolving the inflammation underlying many cardiovascular diseases.
Endothelial inflammation is now appreciated to be a significant contributing factor in many forms of cardiovascular disease and a number of flow-sensitive microRNAs have recently been implicated in the endothelial dysfunction that underlies pathological chronic inflammation. In this proposal we aim to develop a polymeric nanoparticle delivery platform capable of specifically targeting to inflamed endothelial cells (via chemically conjugated antibodies to E-selectin) for the purpose of delivering peptide-nucleic-acid based anti-microRNA agents. If successful, this project will hasten the development of a safe and effective therapy for the chronic inflammation that underlies may forms of cardiovascular disease.
|Jiang, Yuhang; Gaudin, Alice; Zhang, Junwei et al. (2018) A ""top-down"" approach to actuate poly(amine-co-ester) terpolymers for potent and safe mRNA delivery. Biomaterials 176:122-130|