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Clinical trials assessing the potential to treat heart failure using modified mRNA encoding vascular endothelial growth factor-A may have implication for other disorders including cancer

Given the negative impact that COVID-19 coronavirus had on the global population, it is hard not to focus on the 'underlying medical condition' as it continues to serve as the major contributing factor to the associated mortality regardless of the age (ex. under age 65) or the regions affected (ex. India).  According to CDC (U. S. Center for Disease Control), two large-scale studies conducted with >64,000 COVID-19 infected patients have revealed that the major pre-existing comorbidities were disorders affecting circulation (myocardial infarction, chronic pulmonary disease, hyperlipidemia, cardiovascular disease), cancer (metastatic solid tumor), and diabetes. (https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html )  As such, lung's alveolar bronchial cell destruction by COVID-19 may exacerbate the stress on the blood flow and oxygen supply imparted by the pre-existing underlying conditions.

Even before the era of COVID-19 pandemic, myocardial infarction has received much attention as it affects a significant number of people (~1 million cases in the U.S. and Europe annually; nearly 26 million people affected globally).  Myocardial infarction refers to the death of heart muscle cells brought about by the lack of oxygen supply, resulting in heart attack.  Hence, the occlusion of blood flow through the coronary arteries feeding the heart muscles by ruptured plaques (ex. buildup of cholesterol product) or blood clots could lead to the death of the supplied cardiac tissue.  The current methods to control blood pressure/improve heart pumping through drugs, or install pacemaker may not address the root cause of the disorder.

To facilitate heart muscle regeneration, numerous strategies have been deployed including administering of recombinant proteins (ex. erythropoietin to produce red blood cells), regenerative cardiovascular therapies (ex. transplantation of ex vivo amplified cells), etc. though the results have been less than satisfactory.  Among the problems faced were the limited long-term engraftment of cell based therapy, low gene transfer efficacy and the potential for genomic integration by gene (DNA) based therapeutics, immune response to viral delivery vectors, and short half-life of recombinant proteins within the tissue.  Against this backdrop, the 'modified RNA' (incorporating modified nucleotides to avoid innate immunity) has emerged as a potential alternative for treating cardiac disorders.


                    

Mechanistically, prior researches have uncovered that, in normal undamaged heart, heart muscle cells exhibit a turnover rate of ~1.3 - 4% annually, being replaced by the proliferation of pre-existing cardiomyocytes.  After the myocardial infarction, new cells arise from progenitors (stem cells) as well as the pre-existing cardiomyocytes (Malliaras et al., 2013).  Another line of investigation uncovered that following the myocardial infarction, epicardial cells (a sheet of cells covering heart) proliferate and differentiated into muscle cells that secrete paracrine factors, which promote blood vessel formation.  Among the secreted factors was VEGF-A (vascular endothelial growth factor A) (Zhou et al., 2011).

By nature, the expression pattern of modified RNA is 'pulse-like'.  This led K. Chien and his colleagues (Harvard University, USA) to hypothesize that modified RNA may be able to recapitulate the paracrine signals that are transient (as its effects are precisely timed and intended for a specific region).  To assess, modified RNA encoding VEGF-A was constructed incorporating 5-methylcytidine triphosphate and pseudouridine triphosphate, and delivered by myocardial injection at the time of myocardial infarction.  It resulted in the amplification of progenitor cells, followed by their mobilization into the myocardium and differentiating into cardiovascular types (to facilitate blood vessel formation), extending the survival in a mouse model (Zangi et al., 2013).

This has led AstraZeneca to collaborate with Moderna to further the translational research in 2013.  Of noteworthy is their finding that injecting a solution of naked mRNA (without protective coating) may be sufficient for its delivery into the heart in vivo.  By using mRNA, a prolonged expression of VEGF-A, which could precipitate side effects, could be avoided.  This has led to the current Phase 2 clinical trial testing the efficacy of VEGF-A encoding modified RNA in patients with decreased left ventricular function undergoing coronary artery bypass surgery (Anttila et al, 2020).  Likewise, the potential application of modified mRNA to treat cancer is being attempted.

The key to preventing epidemic is the ability to diagnose the infected early to preempt further propagation.  For this, Bio-Synthesis, Inc. provides primers and probes (as well as synthetic RNA control) for COVID-19 diagnosis via RT-PCR assay.  It specializes in oligonucleotide modification and provides an extensive array of chemically modified nucleoside analogues (over ~200) including bridged nucleic acid (BNA).  A number of options are available to label oligonucleotides (DNA or RNA) with fluorophores either terminally or internally as well as to conjugate to peptides or antibodies.  It recently acquired a license from BNA Inc. of Osaka, Japan, for the manufacturing and distribution of BNANC, a third generation of BNA oligonucleotides.  To meet the demands of therapeutic application, its oligonucleotide products are approaching GMP grade.  Bio-Synthesis, Inc. has recently entered into collaborative agreement with Bind Therapeutics, Inc. to synthesize miR-21 blocker using BNA for triple negative breast cancer.  The BNA technology provides superior, unequalled advantages in base stacking, binding affinity, aqueous solubility and nuclease resistance.  It also improves the formation of duplexes and triplexes by reducing the repulsion between the negatively charged phosphates of the oligonucleotide backbone.  Its single-mismatch discriminating power is especially useful for diagnosis (ex. FISH using DNA probe).  For clinical application, BNA oligonucleotide exhibits lesser toxicity than other modified nucleotides. 

https://www.biosyn.com/oligo-flourescent-labeling.aspx

https://www.biosyn.com/tew/Speed-up-Identification-of-COVID19.aspx

https://www.biosyn.com/covid-19.aspx

https://www.biosyn.com/mrna.aspx

 

References

Anttila V, Saraste A, 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. 18:464-472 (2020).  PMID: 32728595

Malliaras K, Zhang Y, et al. Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart.  EMBO Mol Med. 5:191-209 (2013). PMID: 23255322

Zangi L, Chien KR, et al. Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction.  Nat Biotechnol. :898-907 (2013). PMID: 24013197

Zhou B, Honor LB, et al. Adult mouse epicardium modulates myocardial injury by secreting paracrine factors.  J Clin Invest. 121:1894-904 (2011).  PMID: 21505261