Future Impact of mRNA Therapy on Cardiovascular Diseases

John P. Cooke; Keith A. Youker

doi:10.14797/mdcvj.1169

Future Impact of mRNA Therapy on Cardiovascular Diseases

Methodist DeBakey Cardiovascular Journal

Volume 18 (2022): Issue 5

By: John P. Cooke and Keith A. Youker

Open Access

|Dec 2022

Abstract

The silver lining of the recent pandemic was that it accelerated the emergence of messenger ribonucleic acid (mRNA) therapeutics. The great promise of mRNA therapeutics was highlighted by the speed at which the vaccines were created, tested, and proven to be relatively safe and highly effective. There are a wide variety of mRNA therapeutics now under development, and dozens of these are in clinical trials. These therapeutics are generating a major paradigm shift in medical therapy, including the treatment of cardiovascular disease. Most of the cardiovascular mRNA therapies are still in preclinical development, although a phase 2a trial of mRNA therapy for myocardial ischemia has been completed with promising results.¹ The application of mRNA therapies to cardiovascular diseases is virtually limitless, and ongoing work includes mRNA therapies for myocardial ischemia, heart failure, arrhythmias, hypercholesterolemia, and arterial occlusive diseases. In addition, mRNA may be used to enhance cell therapies. In the future, mRNA therapies for cardiovascular disease are destined to supplant some of our current biologics and pharmacotherapies and will be used to treat previously untreatable cardiovascular diseases. Furthermore, mRNA therapies can be personalized, and they can be rapidly generated in current Good Manufacturing Practice facilities with a modest footprint, facilitating the rise of hospital-based regional centers of RNA therapeutics.

References

Collén A, Bergenhem N, Carlsson L, et al. VEGFA mRNA for regenerative treatment of heart failure. Nat Rev Drug Discov. 2022 Jan;21(1):79-80. doi: 10.1038/s41573-021-00355-6
Open DOI Search in Google Scholar Back to article
Xu J, Tsanakopoulou M, Magnani CJ, et al. A prebiotically plausible synthesis of pyrimidine β-ribonucleosides and their phosphate derivatives involving photoanomerization. Nat Chem. 2017 Apr;9(4):303-309. doi: 10.1038/nchem.2664
Open DOI Search in Google Scholar Back to article
Kavita K, Breaker RR. Discovering riboswitches: the past and the future. Trends Biochem Sci. 2022 Sep 20;S0968-0004(22)00234-1. doi: 10.1016/j.tibs.2022.08.009
Open DOI Search in Google Scholar Back to article
Ozata DM, Gainetdinov I, Zoch A, O’Carroll D, Zamore PD. PIWI-interacting RNAs: small RNAs with big functions. Nat Rev Genet. 2019 Feb;20(2):89-108. doi: 10.1038/s41576-018-0073-3
Open DOI Search in Google Scholar Back to article
Kuo CC, Hänzelmann S, Sentürk Cetin N, et al. Detection of RNA-DNA binding sites in long noncoding RNAs. Nucleic Acids Res. 2019 Apr 8;47(6):e32. doi: 10.1093/nar/gkz037
Open DOI Search in Google Scholar Back to article
Hawkins PN, Ando Y, Dispenzeri A, Gonzalez-Duarte A, Adams D, Suhr OB. Evolving landscape in the management of transthyretin amyloidosis. Ann Med. 2015;47(8):625-38. doi: 10.3109/07853890.2015.1068949
Open DOI Search in Google Scholar Back to article
Adams D, Gonzalez-Duarte A, O’Riordan WD, et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 5;379(1):11-21. doi: 10.1056/NEJMoa1716153
Open DOI Search in Google Scholar Back to article
Obici L, Berk JL, González-Duarte A, et al. Quality of life outcomes in APOLLO, the phase 3 trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis. Amyloid. 2020 Sep;27(3):153-162. doi: 10.1080/13506129.2020.1730790
Open DOI Search in Google Scholar Back to article
Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med. 2017 Apr 13;376(15):1430-1440. doi: 10.1056/NEJMoa1615758
Open DOI Search in Google Scholar Back to article
Wright RS, Ray KK, Real FJ, et al. Pooled Patient-Level Analysis of Inclisiran Trials in Patients With Familial Hypercholesterolemia or Atherosclerosis. J Am Coll Cardiol. 2021 Mar 9;77(9):1182-1193. doi: 10.1016/j.jacc.2020.12.058
Open DOI Search in Google Scholar Back to article
Wierzbicki AS, Viljoen A. Anti-sense oligonucleotide therapies for the treatment of hyperlipidaemia. Expert Opin Biol Ther. 2016 Sep;16(9):1125-34. doi: 10.1080/14712598.2016.1196182
Open DOI Search in Google Scholar Back to article
HoustonMethodist.org [Internet]. Houston, TX: Houston Methodist; c2022. Center for RNA Therapeutics; 2022 [cited 2022 Oct 21]. Available from: www.houstonmethodist.org/rna-t
Search in Google Scholar Back to article
FDA.gov [Internet]. Silver Spring, MD: US Food and Drug Administration; c2022. FDA Takes Key Action in Fight Against COVID-19 By Issuing Emergency Use Authorization for First COVID-19 Vaccine; 2020 Dec 11 [cited 2022 Oct 24]. Available from: https://www.fda.gov/news-events/press-announcements/fda-takes-key-action-fight-against-covid-19-issuing-emergency-use-authorization-first-covid-19
Search in Google Scholar Back to article
CEPI.net [Internet]. Washington, DC: CEPI; c2022. 100 days mission; 2022 [cited 2022 Oct 24]. Available from: https://100days.cepi.net/
Search in Google Scholar Back to article
Terada Y, Kawachi K, Matsuura Y, Kamitani W. MERS coronavirus nsp1 participates in an efficient propagation through a specific interaction with viral RNA. Virology. 2017 Nov;511:95-105. doi: 10.1016/j.virol.2017.08.026
Open DOI Search in Google Scholar Back to article
Shehata MM, Kandeil A, Mostafa A, et al. A Recombinant Influenza A/H1N1 Carrying A Short Immunogenic Peptide of MERS-CoV as Bivalent Vaccine in BALB/c Mice. Pathogens. 2019 Dec 2;8(4):281. doi: 10.3390/pathogens8040281
Open DOI Search in Google Scholar Back to article
Karikó K, Buckstein M, Ni H, Weissman D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity. 2005 Aug;23(2):165-75. doi: 10.1016/j.immuni.2005.06.008
Open DOI Search in Google Scholar Back to article
Geall AJ, Verma A, Otten GR, et al. Nonviral delivery of self-amplifying RNA vaccines. Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14604-9. doi: 10.1073/pnas.1209367109
Open DOI Search in Google Scholar Back to article
Stewart DJ, Kutryk MJB, Fitchett D, et al. VEGF gene therapy fails to improve perfusion of ischemic myocardium in patients with advanced coronary disease: results of the NORTHERN trial. Mol Ther. 2009 Jun;17(6):1109-15. doi: 10.1038/mt.2009.70
Open DOI Search in Google Scholar Back to article
Stewart DJ, Hilton JD, Arnold JMO, et al. Angiogenic gene therapy in patients with nonrevascularizable ischemic heart disease: a phase 2 randomized, controlled trial of AdVEGF(121) (AdVEGF121) versus maximum medical treatment. Gene Ther. 2006 Nov;13(21):1503-11. doi: 10.1038/sj.gt.3302802
Open DOI Search in Google Scholar Back to article
Zangi L, Lui KO, von Gise A, et al. Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nat Biotechnol. 2013 Oct;31(10):898-907. doi: 10.1038/nbt.2682
Open DOI Search in Google Scholar Back to article
Gan LM, Lagerström-Fermér M, Carlsson LG, et al. Intradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes. Nat Commun. 2019 Feb 20;10(1):871. doi: 10.1038/s41467-019-08852-4
Open DOI Search in Google Scholar Back to article
Anttila V, Saraste A, Knuuti J, et al. Synthetic mRNA Encoding VEGF-A in Patients Undergoing Coronary Artery Bypass Grafting: Design of a Phase 2a Clinical Trial. Mol Ther Methods Clin Dev. 2020 Jun 1;18:464-472. doi: 10.1016/j.omtm.2020.05.030
Open DOI Search in Google Scholar Back to article
Liu S, Tang L, Zhao X, et al. Yap Promotes Noncanonical Wnt Signals From Cardiomyocytes for Heart Regeneration. Circ Res. 2021 Oct;129(8):782-797. doi: 10.1161/CIRCRESAHA.121.318966
Open DOI Search in Google Scholar Back to article
Kapoor N, Liang W, Marbán E, Cho HC. Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18. Nat Biotechnol. 2013 Jan;31(1):54-62. doi: 10.1038/nbt.2465
Open DOI Search in Google Scholar Back to article
Bai Y, Kan S, Zhou S, et al. Enhancement of the in vivo persistence and antitumor efficacy of CD19 chimeric antigen receptor T cells through the delivery of modified TERT mRNA. Cell Discov. 2015 Dec 8;1:15040. doi: 10.1038/celldisc.2015.40
Open DOI Search in Google Scholar Back to article
Li Y, Zhou G, Bruno IG, et al. Transient introduction of human telomerase mRNA improves hallmarks of progeria cells. Aging Cell. 2019 Aug;18(4):e12979. doi: 10.1111/acel.12979
Open DOI Search in Google Scholar Back to article
Mojiri A, Walther BK, Jiang C, et al. Telomerase therapy reverses vascular senescence and extends lifespan in progeria mice. Eur Heart J. 2021 Nov 7;42(42):4352-4369. doi: 10.1093/eurheartj/ehab547
Open DOI Search in Google Scholar Back to article
Dzul-Huchim VM, Ramirez-Sierra MJ, Martinez-Vega PP, et al. Vaccine-linked chemotherapy with a low dose of benznidazole plus a bivalent recombinant protein vaccine prevents the development of cardiac fibrosis caused by Trypanosoma cruzi in chronically-infected BALB/c mice. PLoS Negl Trop Dis. 2022 Sep 12;16(9):e0010258. doi: 10.1371/journal.pntd.0010258
Open DOI Search in Google Scholar Back to article
Kim SC, Stice JP, Chen L, et al. Extracellular heat shock protein 60, cardiac myocytes, and apoptosis. Circ Res. 2009 Dec 4;105(12):1186-95. doi: 10.1161/CIRCRESAHA.109.209643
Open DOI Search in Google Scholar Back to article
Youker KA, Shen H, Bhimaraj A, Torre-Amione G. Abstract 11435: A New Paradigm in Therapy: A Vaccine Against the Progression of Heart Failure. Circulation. 2021 Nov;144(Suppl 1):A11435. doi: 10.1161/circ.144.suppl_1.11435
Open DOI Search in Google Scholar Back to article
Vogel AB, Lambert L, Kinnear E, et al. Self-Amplifying RNA Vaccines Give Equivalent Protection against Influenza to mRNA Vaccines but at Much Lower Doses. Mol Ther. 2018 Feb 7;26(2):446-455. doi: 10.1016/j.ymthe.2017.11.017
Open DOI Search in Google Scholar Back to article
Beissert T, Perkovic M, Vogel A, et al. A Trans-amplifying RNA Vaccine Strategy for Induction of Potent Protective Immunity. Mol Ther. 2020 Jan 8;28(1):119-128. doi: 10.1016/j.ymthe.2019.09.009
Open DOI Search in Google Scholar Back to article
Lu D, Chatterjee S, Xiao K, et al. A circular RNA derived from the insulin receptor locus protects against doxorubicin-induced cardiotoxicity. Eur Heart J. 2022 Jun 27;ehac337. doi: 10.1093/eurheartj/ehac337
Open DOI Search in Google Scholar Back to article
Boada C, Zinger A, Tsao C, et al. Rapamycin-Loaded Biomimetic Nanoparticles Reverse Vascular Inflammation. Circ Res. 2020 Jan 3;126(1):25-37. doi: 10.1161/CIRCRESAHA.119.315185
Open DOI Search in Google Scholar Back to article
Rurik JG, Epstein JA. Uniting Disciplines to Develop Therapeutics: Targeted mRNA Lipid Nanoparticles Reprogram the Immune System In Vivo to Treat Heart Disease. DNA Cell Biol. 2022 Jun;41(6):539-543. doi: 10.1089/dna.2022.0171
Open DOI Search in Google Scholar Back to article

Articles in this issue

DOI: https://doi.org/10.14797/mdcvj.1169 | Journal eISSN: 1947-6108

Journal RSS Feed

Language: English

Page range: 64 - 73

Submitted on: Oct 11, 2022

Accepted on: Oct 19, 2022

Published on: Dec 6, 2022

Published by: Houston Methodist DeBakey Heart & Vascular Center

In partnership with: Paradigm Publishing Services

Keywords:

myocardial infarction,

heart failure,

arrhythmias,

hypercholesterolemia,

senescence,

telomerase,

vaccine

© 2022 John P. Cooke, Keith A. Youker, published by Houston Methodist DeBakey Heart & Vascular Center
This work is licensed under the Creative Commons Attribution-NonCommercial 4.0 License.

Volume 18 (2022): Issue 5