Vaccine Formulation Strategies and Challenges Involved in RNA Delivery for Modulating Biomarkers of Cardiovascular Diseases: A Race from Laboratory to Market
Abstract
:1. Introduction
2. Therapeutics
2.1. Addressing Pressing Issues of CVD Using miRNA Inhibitors
2.2. Antisense Oligonucleotides (ASO)
2.3. siRNAs and other Inhibitory Techniques
2.4. Antagomirs as Therapeutic Agents
2.5. CVD Treatment with lncRNA Inhibition
3. Pharmaceutics of RNA-Based Vaccine Delivery
3.1. Hurdles in the Systemic Delivery of siRNA
3.2. Stability in the Circulatory System
3.3. Vascular Endothelium as the Semiselective Barrier
3.4. Extracellular Matrix Diffusion
3.5. Cytoplasmic Delivery
4. Delivery Strategies to Improve the Targeting and Therapeutic Efficacy of Non-Coding RNA-Based Vaccines
4.1. Lipid and Lipid-Based Nanoparticle Vaccines
4.2. Polymer-Based Nanoparticle Vaccines
4.3. Device-Based Methods for RNA Vaccines
4.4. RNA Viral Vector-Mediated Vaccine Delivery
4.5. Vaccine Based on Tissue Enrichment via RNA Therapeutics Modification
4.6. miRNA Encapsulation
5. Challenges Associated with RNA Vaccine Therapy
6. Six Qualities of Vaccine Delivery Systems to Be Clinically Relevant
7. Clinical Angle
8. Challenges Associated with Long Non-Coding RNA Therapeutics
9. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Sr No | Mi RNAs | Disease Implicated in | Model | Mechanisms | Ref. |
---|---|---|---|---|---|
1 | miR-15 | MI | Injury caused by ischemia/reperfusion in pigs and mice | Members of the microRNA-15 family have been shown to regulate mitochondrial activity by targeting proteins such as pyruvate dehydrogenase lipoamide kinase isozyme 4 and checkpoint kinase 1. | [10,11] |
2 | miR-24 | MI | MI mouse model | The miR-24 family member Bcl2 is repressed. One characteristic of miRNA-mediated regulation of critical cellular events is exemplified by the BIM protein. It has been found that miR-24 inhibits apoptosis in cardiomyocytes in a cell-independent manner. | [12] |
3 | miR-34 | MI | Mice | Through its regulation of suppression of the target gene PNUTS (protein phosphatase 1 nuclear-targeting subunit), miR-34a promotes telomere degradation and, by extension, age-related induction of cardiomyocyte cell death. | [13,14,15] |
4 | miR-92a | MI | Inhibits angiogenesis by reducing integrin α5 and sirtuin 1 expression. | [16,17,18] | |
5 | miR-199a | MI | Pig model | Improves cardiac function by stimulating endogenous myocardial repair mechanisms. | [19] |
6 | miR-320 | MI | Ischemia/reperfusion injury | Increased miR-320-3p expression and decreased Akt3 expression were seen in cardiomyocytes after H/R damage. | [20] |
7 | miR-590 | MI | Patient | Regulating SOX4 can help restore the cell cycle process, which in turn boosts cardiomyocyte proliferation and reduces the severity of AMI. | [21] |
8 | miR-29 | Cardiac fibrosis | Adult male and female C57BL/6 mice | Several matrix proteins are targeted by overexpression to reduce fibrosis. | [22] |
9 | miR-21 | Cardiac fibrosis | Mice | Reduces the function of Spry1 (sprouty homologue 1), hence promoting the profibrotic ERK-MAP kinase signalling pathway. | [23] |
10 | miR-1, | Hypertrophy and heart failure | Male Sprague–Dawley rats | Its expression went down by a lot, as did the amount of collagen in the body and the activity of key profibrotic factors can also be involved in regulating fibrosis by going after Fbln2, a secreted ECM protein that plays a crucial part in tissue remodelling in diseased condition. | [24] |
11 | miR-133, | Hypertrophy and heart failure | When miR-133a is misregulated, it inhibits the expression of NFATc4, a mediator of hypertrophy. | [25] | |
12 | miR-208, | Hypertrophy and heart failure | Mice | Overexpression of miR-208 inhibits the muscle-wasting proteins THAP1 and myostatin. | [26] |
13 | miR-25 | Hypertrophy and heart failure | TAC model | Blocking microRNA-25a, cardiac function was restored by inhibiting the calcium uptake pump SERCA2a (sarco/endoplasmic reticulum Ca2+-ATPase 2a), which improved calcium management. | [27] |
14 | miR-212/132 | Hypertrophy and heart failure | TAC mouse model | Inhibits the GFP/SERCA2a-3′-UTR expression. | [28] |
15 | miR-92a | Atherosclerosis and vascular remodelling | Mice | Inhibiting miR-92a, which functions as a proinflammatory regulator in endothelial cells by activating inflammatory cytokines and chemokines and augmenting monocyte adhesion, protects against endothelial dysfunction. | [29] |
16 | miR-126 | Atherosclerosis and vascular remodelling | Female C57/BL6 mice | Through an indirect pathway mediated by apoptosis and VCAM-1 expression, suppression of stromal cell-derived factor-1/CXCL12 expression may attenuate leukocyte homing from blood circulation through the endothelium in vivo. | [30] |
17 | miR-146 | Atherosclerosis and vascular remodelling | Patients with aortic valve stenosis | Downstream TLR4 signalling was controlled by a negative-feedback loop that included IL-1 receptor associated kinase 1 (IRAK1) and TNF-receptor associated factor 6 (TRAF6). | [31] |
18 | miR-181 | Atherosclerosis and vascular remodelling | ApoE−/− mice | IB kinase (IKK) complex regulatory/scaffold subunits TAB2 and NEMO are critical for inflammation-induced canonical NF-κB activation, which leads to the phosphorylation and degradation of IBs and the nuclear translocation of p65, thereby inhibiting vascular inflammation. | [32] |
Sr No | lnc RNAs | Disease Implicated in | Model | Mechanisms | Ref. |
---|---|---|---|---|---|
1 | Malat-1 | MI | Postinfarct myocardium mice model | Post-MI, induced endothelial cell proliferation and ischemia-induced revascularization promoted by miR-145 regulation of TGF-1 expression cause cardiac fibrosis and decrease cardiac function. | [58,63] |
2 | lincRNA-p21 | Atherosclerosis | Carotid artery injury model | Modulator of cell death by inhibiting p53 transcription during atherosclerosis is inhibited by lentivirus-mediated siRNA release targeting lincRNA-p21, causing neointima hyperplasia. | [60] |
3 | MIAT | MI | Mice | A molecular sponge for miR-15097 and a target gene modulator for the fibrosis-related factors miR-24, furin, and TGF-β1. | [58,64] |
4 | CARL | MI | Rat | Block particular microRNAs to control cardiomyocyte cell death. | [65] |
5 | CHRF | Cardiac hypertrophy | Transgenic mice that overexpress miR-489 in the heart | Directly bind miR-489 and control expression of MyD88 and hypertrophy. | [66] |
6 | Chast | Cardiac hypertrophy | TAC-operated mice | Repression of the pleckstrin homology domain containing protein family M member 1 promotes hypertrophy and prevents autophagy in cardiomyocytes. | [67] |
7 | Mhrt | Cardiac hypertrophy | TAC-operated mice | Mhrt activity is inhibited under pathological stress situations including pressure overload–induced hypertrophy and interferes with chromatin remodelling factor Brg1, regulating its target genes Myh6, Myh7, and osteopontin. | [68,69] |
8 | Meg3 | Cardiac hypertrophy | C57BL6 mice | MMP-2 upregulation in cardiac fibroblasts induced cardiac fibrosis and diastolic dysfunction. | [59,70]. |
9 | lncRNA H19 | Coronary artery disease | Mice | Induced through vascular damage and human atherosclerotic plaques. | [71] |
10 | linc00323-003 | Atherosclerosis | Inhibit the transcription of GATA2 (GATA-binding protein 2), a critical endothelial transcription factor that may control cell sproliferation and tube formation. | [72] |
Vaccines | Type | Clinical Trial | Ref | |
---|---|---|---|---|
TQJ230 (AKCEA-APO(a)-LRx), | Lipoprotein mRNA-specific ASO | Lowering of lipoprotein | Phase II | [181] |
Volanesorsen | ASO | This ASO, which can be given subcutaneously, inhibits APOC3 mRNA stability by binding to it. Apoc-II was reduced by 80%, triglycerides by 71%, and HDL-C by 46%. | Phase II | [213] |
CDR 132L | ASO | Heart failure | Phase I | [214] |
MRG-110 | ASO | Heart failure and ischemia; wounds (NDR) | Phase I (no development reported) (NDR) | [215] |
SPC 4955 | ASO | Hypercholesterolemia | Discontinued | [215] |
SPC 5001 | ASO | Hypercholesterolemia | Discontinued | [216] |
ISIS CRPRx | ASO | Atrial fibrillation | Discontinued | [217] |
ARO APOC3 | siRNA | Dyslipidemias; hypertriglyceridemia (II); hyperlipoproteinemia type I (III) | Phase III; phase II | [218] |
Zilebesiran | siRNA | Hypertension (II); preeclampsia (NDR) | Phase II; no development reported | [219] |
Olpasiran | siRNA | CVD | Phase II | [220] |
LY 3,561,774 | siRNA | CVD; dyslipidaemias; metabolic disorders | Phase I | [221] |
LY 3,819,469 | siRNA | CVD; metabolic disorders | Phase I | [222] |
SLN 360 | siRNA | CVD (Pre); dyslipidaemias; hyperlipidaemia(I) | Preclinical; phase I | [223] |
miR132-3p-inhibitor (CDR132L) | miR | Stable heart failure | Phase I | [224] |
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Shaharyar, M.A.; Bhowmik, R.; Al-Abbasi, F.A.; AlGhamdi, S.A.; Alghamdi, A.M.; Sarkar, A.; Kazmi, I.; Karmakar, S. Vaccine Formulation Strategies and Challenges Involved in RNA Delivery for Modulating Biomarkers of Cardiovascular Diseases: A Race from Laboratory to Market. Vaccines 2023, 11, 241. https://doi.org/10.3390/vaccines11020241
Shaharyar MA, Bhowmik R, Al-Abbasi FA, AlGhamdi SA, Alghamdi AM, Sarkar A, Kazmi I, Karmakar S. Vaccine Formulation Strategies and Challenges Involved in RNA Delivery for Modulating Biomarkers of Cardiovascular Diseases: A Race from Laboratory to Market. Vaccines. 2023; 11(2):241. https://doi.org/10.3390/vaccines11020241
Chicago/Turabian StyleShaharyar, Md. Adil, Rudranil Bhowmik, Fahad A. Al-Abbasi, Shareefa A. AlGhamdi, Amira M. Alghamdi, Arnab Sarkar, Imran Kazmi, and Sanmoy Karmakar. 2023. "Vaccine Formulation Strategies and Challenges Involved in RNA Delivery for Modulating Biomarkers of Cardiovascular Diseases: A Race from Laboratory to Market" Vaccines 11, no. 2: 241. https://doi.org/10.3390/vaccines11020241
APA StyleShaharyar, M. A., Bhowmik, R., Al-Abbasi, F. A., AlGhamdi, S. A., Alghamdi, A. M., Sarkar, A., Kazmi, I., & Karmakar, S. (2023). Vaccine Formulation Strategies and Challenges Involved in RNA Delivery for Modulating Biomarkers of Cardiovascular Diseases: A Race from Laboratory to Market. Vaccines, 11(2), 241. https://doi.org/10.3390/vaccines11020241