Towards microRNA-based therapeutics for cardiovascular diseases

Abstract

Cardiovascular diseases are still one of the leading causes of morbidity and mortality worldwide. The major risk factors currently associated with cardiovascular diseases will continuously increase these numbers, especially in developing countries, which will lead to a steep increase in mortality rates. This worldwide growing burden of cardiovascular diseases prompts to continuously search for new therapeutic possibilities, which definitively demand a better understanding of the molecular mechanism underlying cardiovascular diseases. The aim of this thesis was to identify novel miRNA targets that are involved in cardiovascular diseases and explore the feasibility of using specific miRNA therapeutics for interventions. To search for novel miRNA targets, we have applied state of art technology to identify dynamic regulated microRNAs in cardiovascular disease models. To understand the biological role of these microRNAs, we used various techniques including a multicolor microRNA in situ hybridization technique, a microRNA-free Simple cell system for targets identification and individual microRNA functional studies and use of transgenic knockout mice models to study the mechanistic role of microRNAs. Our studies show that one microRNA can play different roles under different tissue or cellular context. These observations suggest that targeted tissue or organ-specific delivery might be essential for microRNA based interventions. To further explore the possibility of targeted delivery, we designed and tested new delivery systems, including ultrasound-exposed microbubbles and nanopolymers for targeted delivery of microRNA therapeutics in the cardiovascular system.

With more and more miRNAs being identified to be involved in different processes of cardiovascular diseases in preclinical discoveries influencing angiogenesis, fibrosis, cardiomyocyte hypertrophy, cell death and many others, we foresee that miRNA therapeutics will take a great leap towards clinic testing. Along with the already ongoing clinical trial, new strategies in microRNA based therapeutics will continuously evolve as well. For instance, the second generation miRNA mimics with single strand miRNA structural design such as agomiR will significantly push the application of miRNA mimics forward. In order to target complicated diseases such as cardiovascular disease, the usage of cocktails to manipulate several miRNAs will be necessary. Finally, the usage of miRNA therapeutics in combination with other established therapies, such as heart transplantation or stem cell therapy, will be available. In either of these applications, fundamental understanding of miRNA biology as well as its targeted delivery strategies will be key for the successful application of miRNA therapeutics in clinic.