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Applying mRNA based technology to express a surplus of decoy ACE2 receptors to prevent COVID-19 infection

There has been an increased interest in mRNA technology due to the roll out of mRNA based vaccines for COVID-19 prevention.  The expected resurgence of COVID-19 in the latter part of 2020 did materialize and the number of deaths has risen to a level previously encountered in April of 2020.  In the state of California, the deaths associated with COVID-19 have exceeded the level observed in early 2020, hastening the call for the speedier distribution of the mRNA vaccines.  The underlying reason is unclear though the emergence of a novel strain of COVID-19 remains a possibility.  Aside from the mRNA vaccines, which has also been used to induce immunity against cancer, multiple other types of vaccines are currently under development against COVID-19.

Of interest is the non-immunological application of mRNA technology to counter the COVID-19 pandemic.  Human angiotensin-converting enzyme 2 (ACE2) was identified as the receptor for COVID-19 in keeping with the prior finding that it represents the receptor for HCoV-NL63 and SARS-causing coronaviruses.  Docking of the spike protein (of COVID-19) to ACE2 allows the endocytosis of the bound complex.  This has prompted the development of various peptides and peptide mimetics targeting either the spike protein or ACE2 to disrupt the COVID-19 entry (VanPatten, et al 2020).  The therapeutic efficacy of multiple peptide drugs against COVID-19 is being assessed through clinical trials.

An alternative to the above approach involves expressing a surplus of decoy receptors to divert COVID-19 away from respiratory cells.  Of relevance, in 2013, soluble form of recombinant human ACE2 (hrsACE2) has been tested for treating patients afflicted with pathologically high level of angiotensin II (as ACE2 converts angiotensin II to angiotensin I) (Haschke et al., 2013).   In 2017, it was further tested to treat patients with acute respiratory distress syndrome (Khan et al., 2017).  After the emergence of COVID-19 coronavirus in 2020,  the investigators at the Karolinska Institute and Karolinska University Hospital (Sweden) reported that clinical grade of hrsACE2 could suppress the infection of human kidney organoids (organ-like structures formed in vitro from progenitor cells) by COVID-19 (Montell et al., 2020).



A drawback to the above methodology is that hrsACE2 exhibits relatively short half-life in circulation, requiring multiple administrations for extended periods to treat the COVID-19 infected.  To improve, an mRNA was designed to ectopically express human ACE2 after transfection, which could then be secreted to the extracellular milieu (Kim et al., 2020).  The ACE2-encoding mRNAs produced by in vitro translation were packaged in lipid-based nanoparticles for the cellular uptake.  Its systemic injection resulted in the hepatic delivery, followed by the secreted ACE2 which was detectable in the circulation.   Nevertheless, it remains to be seen whether the mRNA transfected cells expressing secreted ACE2 in vivo constitute a novel target for COVID-19 coronavirus. 

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 conjugate to peptidesIt 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.’-O-methylation,-“self-and-non-self,”-and-Coronaviruses.aspx



Haschke M, Schuster M, et al. Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting enzyme 2 in healthy human subjects.   Clin Pharmacokinet. 52:783-92 (2013). PMID: 23681967

Khan A, Benthin C, et al. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome.   Crit Care. 21:234 (2017).  PMID: 28877748

Kim J, Mukherjee A, et al. Rapid generation of circulating and mucosal decoy ACE2 using mRNA nanotherapeutics for the potential treatment of SARS-CoV-2.  bioRxiv. 2020 Jul 25.   PMID: 32743574

Monteil V, Kwon H, et al. Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2.  Cell  181:905-913.e7 (2020).  PMID: 32333836

VanPatten S, He M, Altiti A, et al. Evidence supporting the use of peptides and peptidomimetics as potential SARS-CoV-2 (COVID-19) therapeutics.   Future Med Chem. 12:1647-1656 (2020).  PMID: 32672061