Modified mRNA Therapeutics for Heart Diseases
Abstract
:1. Introduction
2. modRNA Technology Development and Delivery
- The optimum uptake of the nucleic acid by cardiac cells;
- The optimum expression and time of expression of nucleic acid;
- Minimum or no immune response in the heart;
- Efficient translation, stability, and transfection of the gene in the heart;
- The delivery material should be safe and not interfere with gene function.
3. Cardiomyocyte-Specific modRNA Expression in the Heart
4. modRNA in Cardiomyocyte Proliferation
5. Cardiomyocyte Apoptosis and Survival
6. modRNA in Cardiac Inflammation
7. modRNA in Cardiac Oxidative Stress
8. modRNA in Cardiac Metabolism
9. modRNA in Cardiac Angiogenesis
10. Future of modRNA Therapy in Heart Diseases
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
MI | myocardial infarction |
HF | heart failure |
iPSCs | induced pluripotent stem cells |
hiPSC-CMs | human-induced pluripotent stem cell-derived cardiomyocytes |
ROS | reactive oxygen species |
miRNA | microRNA |
CVD | cardiovascular diseases |
CM | cardiomyocyte |
FDA | Food and Drug Administration |
ARCA | anti-reverse cap analog |
PPP | pentose phosphate pathway |
IGF-1 | insulin growth factor 1 |
YAP | yes-associated protein |
TNF-α | tumor necrosis factor-α |
Pkm2 | pyruvate kinase isozyme 2 |
G6PD | glucose-6-phosphate dehydrogenase |
ihCD25 | inactive human CD25 |
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Sr. No. | Character | Plasmid | Protein | Adenovirus | Lentivirus | AAV | ModRNA |
---|---|---|---|---|---|---|---|
1 | Genome type | DNA | Protein (amino acids) | Double stranded DNA | DNA | Single stranded RNA | Single stranded mRNA |
2 | Size (diameter) | ---- | ---- | 100 | 90 nm | 20 nm | ---- |
3 | Expression duration | 1–4 weeks | Hours | 1–4 weeks | Long-term | Long-term (months to years) | 7–12 days |
4 | Peak expression in the heart | 2–4 days | Hours | 2–4 days | 4–6 days | 2–4 weeks | 1–2 days |
5 | Transfection | Low | ---- | High | Low | High | High |
6 | Synthesis time | Short–moderate | Short–moderate | Moderate | Moderate | Moderate | Short |
7 | Immune response | Mild | No | Severe | Moderate | Mild | Low |
8 | Gene insert | Limited | ---- | 1–2 genes | 2–8 genes | 1–2 genes | Unlimited |
9 | Genomic integration | Yes | No | Yes | Yes | Yes | No |
10 | Tissue or cell specificity | No | No | No | No | Yes | Yes/No |
11 | Delivery | Lipid | Direct | Direct | Lipid | Direct | Lipid, saline, nanomaterial |
12 | Delivery method | Direct | Direct or IV | Direct | Direct | Direct or IV | Direct |
13 | Clinical application | Very low | Moderate | Very low | Very low | Moderate to high | High |
14 | Human clinical trials in heart diseases (NCT02935712) | ---- | ---- | ---- | ---- | <5 | 1 |
Sr. No. | Publication | Gene/Genes | Study and Role | Animal/Cells |
---|---|---|---|---|
1 | Chen et al. [39] | aYAP | Reduction of cardiac inflammation and hypertrophy | Cardiac cells/Mice |
2 | Sultana et al. [37] | Luc/GFP | Optimization of 5’ untranslated region and modRNA expression in the heart | Cardiac cells/Mice |
3 | Magadum et al. [13] | Pkm2 | Cardiomyocyte-specific modRNA expression, cardiomyocyte proliferation and cardiac regeneration | Cardiac cells/Mice |
4 | Carlsson et al. [40] | VEGFa | Increase of angiogenesis, reduction of fibrosis and improvement of cardiac function post MI | Cells, Pig, Monkey |
5 | Hadas et al. [36] | Acid ceramidase | Inhibition of cardiomyocyte apoptosis, improved cardiac function | Cardiac cells/Mice |
6 | Hadas et al. [41] | Luc/GFP | Optimization of modified mRNA in vitro synthesis protocol for heart gene therapy | Cardiac cells/Mice |
7 | Singh et al. [42] | EGFP, mCherry, Fluc | Microencapsulated modRNA expression in the heart | Mice, Pig |
8 | Magadum et al. [12] | Mutated FSTL1 | Cardiomyocyte proliferation, reduction of scar size and improvement of cardiac function post-MI | Cardiac cells/Mice |
9 | Sultana et al. [33] | Luc/GFP | Optimization of modRNA expression | Cardiac cells/Mice |
10 | Turnbull et al. [15] | EGFP | modRNA expression in the heart | Rat and Pig |
11 | Zangi et al. [32] | IGFR, DN-IGF-1R | Inhibition of adipogenic differentiation post-MI | Mice |
12 | Kondrat et al. [43] | Luc/GFP | modRNA synthesis | In vitro/Mice |
13 | Turnbull et al. [44] | EGFP | Lipidoid mRNA nanoparticles protocol | Rodents |
14 | Huang et al. [34] | IGF-1 | Inhibition of cardiomyocyte apoptosis and survival cardiomyocytes | Mice |
15 | Lui at al. [45] | VEGFa | Promotion of Isl1+ to endothelial cell fate, survival and proliferation of Isl1+ progenitors | Mice |
16 | Zangi et al. [35] | VEGFa | Inducement of vascular regeneration and cellular fate switch | Cardiac cells/Mice |
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Magadum, A. Modified mRNA Therapeutics for Heart Diseases. Int. J. Mol. Sci. 2022, 23, 15514. https://doi.org/10.3390/ijms232415514
Magadum A. Modified mRNA Therapeutics for Heart Diseases. International Journal of Molecular Sciences. 2022; 23(24):15514. https://doi.org/10.3390/ijms232415514
Chicago/Turabian StyleMagadum, Ajit. 2022. "Modified mRNA Therapeutics for Heart Diseases" International Journal of Molecular Sciences 23, no. 24: 15514. https://doi.org/10.3390/ijms232415514
APA StyleMagadum, A. (2022). Modified mRNA Therapeutics for Heart Diseases. International Journal of Molecular Sciences, 23(24), 15514. https://doi.org/10.3390/ijms232415514