Highlights
The Ministry of Health of the Russian Federation has approved MIR 19, a new antiviral drug indicated for the treatment of COVID-19 infection caused by the SARS-CoV-2 coronavirus.
MIR 19 inhibits coronavirus replication and prevents the development of severe COVID including acute respiratory distress syndrome (ARDS).
MIR 19 is approved for the treatment of adult patients with non-serious COVID-19.
MIR 19 is administered in inpatient settings by inhalation with a nebulizer, twice a day, 15–20 minutes for each inhalation, a 14-day course.
MIR 19 was developed by the Russia-based Institute of Immunology of the Federal Medical and Biological Agency (FMBA).
MIR 19: Mechanism of Action
Almost all RNA-containing viruses (except retroviruses) — SARS-CoV-2 is one of them — turn to RNA-dependent RNA polymerase (RdRp, RNA replicase) for their replication. This critical enzyme for the life cycle of the virus catalyzes RNA replication — the synthesis of new RNAs complementary to the existing RNA matrix encoded in the virus genome. Problem-free RNA replication is necessary for further synthesis of virus components (structural and nonstructural proteins, genome) and virion assembly.
Obviously, if RdRp is compromised, the life cycle of the virus will be disrupted. This is what MIR 19 does.
The mechanism of action of MIR 19 refers to RNA interference (RNAi), a natural mechanism of silencing (suppression of expression) of genes at the stage of transcription, translation, deadenylation, or degradation of matrix RNA (mRNA) using small interfering RNA (siRNA).
Synthetic siRNA sequences within MIR 19 (codenamed siCoV or siRk-12) target nonstructural protein 12 (Nsp12), a region in the SARS-CoV-2 genome that encodes RdRp.
Dendrimer cationic peptides (codenamed KK-46) are used for targeted delivery of miRNAs into cells. They form complexes with negatively charged miRNAs and condense them into compact nanostructures, and this, on the one hand, protects miRNAs from the cleavage action of nucleases and, on the other hand, promotes translocation of miRNAs across cell membranes by endocytosis. In MIR 19, these peptides are presented in excess, thus providing a total positive charge of the entire therapeutic complex, which increases the efficiency of its penetration into cells, since the cell surface normally carries a negative charge.
Since the RdRp genetic sequence is highly conserved (i.e., unlikely to ever seriously change) throughout the entire RNA virus superfamily (except for retroviruses), its selection as a target for MIR 19 is justified: the drug will remain effective no matter which SARS-CoV-2 variant it has to deal with, including Omicron or Delta.
Given that MIR 19 deals with suppression of viral replication, it should be used in the earliest stages of symptoms and signs of COVID-19, in the first days. As time passes, the effectiveness of MIR 19 will decrease dramatically, because the course of COVID-19 is no longer mainly dependent on the presence of coronavirus per se, but on the immune reactions caused by it and attacking the body.
This is confirmed by the antiviral drug Veklury (remdesivir) by Gilead Sciences, which, being directed against RdRp (but with a different mechanism of action), is effective only in the first days of COVID-19 progression. The same is true for favipiravir.
The MIR 19 kit contains four vials (miRNA and carrier peptide lyophilisates, two buffer solutions), which must be mixed immediately before use to prepare an inhalation solution.
Overall, the mechanism of action of MIR 19 raises no doubts about its reasonableness, adequacy, and justification. First, the inhaled administration of MIR 19 is due to the fact that SARS-CoV-2 replicates abundantly in the upper and lower respiratory tract epithelium because of the high expression of angiotensin-converting enzyme 2 (ACE2) as a cellular entry point for the virus.
Second, the choice of RNA-dependent RNA polymerase as a therapeutic target is confirmed by the successful example of remdesivir, on which Gilead is making billions of dollars.
Third, the use of RNA interference as a therapeutic modality has found its way into the following four commercialized drugs (the first three released by Alnylam Pharmaceuticals, the fourth proposed by Novartis):
- Onpattro (patisiran) to treat hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (hATTR-PN), also known as familial amyloid polyneuropathy (FAP)
- Givlaari (givosiran) to treat acute hepatic porphyria (AHP)
- Oxlumo (lumasiran) to treat primary hyperoxaluria type 1(PH1)
- Leqvio (inclisiran) for lowering low-density lipoprotein (LDL) cholesterol levels in primary hypercholesterolemia, mixed dyslipidemia, atherosclerotic cardiovascular disease (ASCVD).
MIR 19: Clinical Trials
MIR 19 has completed a phase 1 clinical trial involving 50 volunteers. A phase 2 clinical trial enrolling 317 COVID-19 patients has not yet been completed. Scientific data regarding the safety and efficacy of MIR 19 for human use have not yet been disclosed.
A scientific article describing the preclinical effects of COVID-19 RNA interference therapy on Vero E6 cell lines and animal models of Syrian hamsters infected with SARS-CoV-2 has been published. The beneficial effects of reducing viral load and decreasing pathological changes in lung tissue were confirmed.
MIR 19: What’s Next
Considering that MIR 19 suppresses replication of SARS-CoV-2 coronavirus, reduces viral load, alleviates COVID-19 symptoms, reduces risks of airborne transmission and clinical complications, MIR 19 continues to be studied for outpatient use. This will open new possibilities in the fight against COVID-19.
First, the drug can be used at home (a nebulizer is not difficult to buy), thereby reducing the risk of a severe course of COVID-19 followed by hospitalization.
Second, MIR 19 will come in handy in the task of COVID-19 post-exposure prevention: if unsafe contact with COVID-19 infected individuals is suspected, it is sufficient to perform a prophylactic inhalation of the drug.
It is currently not possible to buy MIR 19 freely: the drug will be available at hospital facilities as soon as it passes all necessary approval procedures. MIR 19 will be available in retail pharmacies only after it has undergone appropriate clinical trials in outpatients with COVID-19.