mRNA-Based Therapy for the Heart
Heart disease, such as myocardial infarction (MI) and heart failure (HF) remains the leading cause of mortality for the human population. The adult mammalian heart is one of the least regenerative organs in the human body, mainly due to cell-cycle arrest in cardiomyocytes (CMs). In a new era of vascular and cardiac regeneration research, researchers focus on the repair and regeneration of tissues using gene-based therapy. In recent, DNA-based or viral approaches for cardiac gene delivery has encountered major challenges due to their poor and uncontrolled delivery of the targeted genes. With extensive research and technical progress in the field of mRNA, modified mRNA (modRNA) has emerged as safe, efficient, non-immunogenic, and controlled nucleic acid delivery system for various organs, including the heart. Here, we give a brief introduction to mRNA-based therapeutics for the heart, hoping to promote the application of such treatment to heart diseases. Notably, Creative Biogene is offering a wide series of mRNA research services, which can accelerate the progress of mRNA-based cardiac treatment for customers worldwide.
Current approaches in cardiac gene-based therapy
Gene-based therapy is to transplant normal genes into cells to substitute for defective or miss genes, aiming to correct genetic disorders or promoting a beneficial mechanism or pathway of inactivity. With the increasing understanding of the cardiac disease, the use of gene-based therapies to treat coronary heart disease is attracted more and more attention. In the past decades, great advances have been made in the delivery of nucleic acids into the heart by viral and non-viral vectors.
Since lentiviral vectors can transduce non-dividing CMs, they are applied for cardiac gene therapy by researchers. However, their chief advantages come with side effects, as leading a risk of compromising the genome and tumorigenesis. As gene delivery vectors, adenoviruses and adeno-associated viruses (AAVs) have been the most widely used for cardiovascular applications, because of their exceptional transduction efficiencies. Adenoviruses can transfer genes efficiently and transiently into the myocardium in large animals but trigger a strong immune response. And AAV-mediated delivery has low immunogenicity, therefore, is widely used as an alternative to gene delivery for the heart.
Myocardial infarction (MI) leads to a massive loss of cardiomyocytes (CMs), which are replaced with highly proliferating fibroblasts, resulting in scarring of heart tissue in the affected areas, in most cases, lead to heart failure (HF). mRNA has emerged as an attractive tool for protecting MI survivors against HF via targeting several mechanisms. It is reported that there are three main strategies for modRNA in the treatment of ischemic injury, inducing.
Direct cardiac repair using modRNA system to deliver genes involved in inducing cardiomyocyte proliferation, cardiomyocyte protection, and cardiovascular regeneration. (Kaur, K., & Zangi, L., 2020).
- CM proliferation by modRNA
- ModRNA offers cardiac protection via inhibiting heart cell death and attenuating inflammation
- Supporting cardiovascular regeneration
During MI, modRNA is an effective delivery system for re-awakening CM proliferation. It is reported that modRNA can induce CM proliferation and regeneration via promoting the expression of mutated human follistatin-like (hFSTL1). And mutation at position 180 of asparagine (N) with glutamine (Q) (an N-glycosylation site) is the target to activate CM proliferation and reduce cardiac remodeling after myocardial infarction. In addition, CM division can be increased by Pkm2 (pyruvate kinase muscle isoenzyme 2) modRNA delivery. Pkm2 is expressed mainly in regenerated fetal heart and neonatal CMs, but not in adult CMs.
modRNA gene delivery has the potential to enact an extended cytoprotective effect by transient expression of proteins, including acid ceramidase (AC), transcriptional co-activator yes-associated protein (aYAP), and insulin-like growth factor-1 (IGF1). AC mainly frees fatty acids and sphingosine in ceramide hydrolysis, and elevated levels of this enzyme would reduce the level of detrimental neutrophil in the left ventricle (LV), thus attenuating inflammation related to MI and promoting cell survival. modRNA-mediated transient activation of aYAP protein promotes cell proliferation and reduces IR-induced inflammation by downregulating neutrophil infiltration.
After myocardial infarction, loss of endothelial cells (ECs) and subsequent reduction of vascularization tissue lead to ischemia around the infarction site. To repair this damage, one established way is to regenerate the blood vessels supporting the CMs. Vascular endothelial growth factor-A (VEGF-A) has shown potency as an angiogenic factor after ischemic injury. The delivery of VEGF-A modRNA has the capability to increase the levels of endogenous heart progenitors and promote differentiation of these cells toward cardiovascular lineages. Moreover, modRNA-induced transient expression of VEGF-A can avoid the negative effects of prolonged VEGF-A expression. Compared with plasmid DNA, the mRNA-based method has shown greater advantages in reducing infarct size, enhancing myocardial perfusion, and improving CM survival.
Creative Biogene is a leading service provider for mRNA-based drug research and development. We can support our customers with the most affordable, high-quality custom mRNAs according to the desired applications. For any requested information about our services, please don't hesitate to contact us.
- Kaur, K., & Zangi, L. (2020). "Modified mRNA as a Therapeutic Tool for the Heart." Cardiovascular Drugs and Therapy, 1-10.