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06-2022

Novel nanoligomer approach to treat severe COVID-19

The lack of antiviral treatments for respiratory infections became evident with the emergence and global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Study: Nanoligomers targeting human miRNA for treatment of severe COVID-19 are safe and non-toxic in mice.  Image Credit: cherezoff/Shutterstock.com

To study: Nanoligomers targeting human miRNA for treatment of severe COVID-19 are safe and non-toxic in mice. Image Credit: cherezoff/Shutterstock.com

Background

SARS-CoV-2 is a positive-strand enveloped ribonucleic acid (RNA) virus that binds to the human angiotensin-converting enzyme receptor 2 (ACE2) and transmembrane protease receptor serine 2 (TMPRSS2), both of which They are mainly found in the respiratory tract and lungs. SARS-CoV-2 infection subsequently leads to coronavirus disease 2019 (COVID-19).

Severe cases of COVID-19 can lead to acute respiratory distress syndrome, cytokine storm syndrome, and respiratory failure. COVID-19 can also damage the liver, cardiovascular system, kidneys, gastrointestinal tract, and nervous system.

Although several vaccines against SARS-CoV-2 have been developed, the continuous appearance of new variants, the lack of availability of vaccines and/or low vaccination rates continue to threaten the safety of the world population against COVID-19. In addition to the high mortality rates of COVID-19, the possible long-term effects that have been reported in people who have recovered from the disease are also a considerable public health concern.

Antisense oligonucleotides (ASOs) are single-stranded synthetic nucleotides that can bind organic nucleic acids and molecules such as synthetic small interfering RNAs (siRNAs), peptide nucleic acids (PNAs), and morpholinos.

PNAs consist of nucleobases on a pseudopeptide backbone and have a long live half life. Furthermore, PNAs can bind strongly to both RNA and DNA due to an unloaded backbone and thus can be used as inhibitory therapies that bind much more tightly to their target compared to DNA-based technologies.

Micro-RNAs (miRNAs) are small non-coding RNAs that serve many functions, including post-transcriptional regulation of genes associated with infection. High levels of miRNA 2392 (miR-2392) have been observed in humans as a result of severe SARS-CoV-2 infection.

Furthermore, miR-2392 has also been reported to aid in viral replication and limit the host’s immune response to SARS-Cov-2. Hypoxia, increased inflammation, glycolysis, and mitochondrial suppression have also been observed with elevated levels of miR-2392.

Previous studies have reported that PNAs can bind to miRNAs and modulate immune responses, detect biomarkers, fight tumors, or serve as bio-supramolecular tags. However, the use of antisense technologies presents several challenges, since nucleic acids require a delivery vehicle to be able to pass into cells.

One approach to overcome this challenge may be the use of nano-ligomers. Nanoligomers contain gold nanoparticles that enhance its transport and distribution throughout the body.

Previous studies with nanoligomers have indicated lower levels of SARS-CoV-2, as well as no toxicity, making them a suitable treatment option. However, more knowledge about its live biodistribution, safety and pharmacokinetics (PK).

a new ACS Biomaterials Science and Engineering The study examines the biodistribution and safety of a novel nanoligomer called SBCoV207, which was used to target miR-2392 in a mouse model.

About the study

The current study involved the design and synthesis of nanoligomers followed by surface plasmon resonance (SPR) measurements. SARS-CoV-2 was propagated and viral titers were determined by plaque assay on Vero E6 cells. This was followed by a quantitative reverse transcription polymerase chain reaction (PCR) assay to measure SARS-CoV-2 RNA levels as well as immunofluorescence of viral nucleocapsid (N) protein.

A five-day intranasal safety study was conducted in female BALB/c mice that were eight to 12 weeks old. SBCoV207 doses of 1, 2, 5, or 10 mg/kg were administered to each group intranasally and monitored for five days before euthanasia.

Blood and urine samples were collected before euthanasia, while tissue samples were collected afterward. Enzyme-linked immunosorbent assay (ELISA) was used to determine serum levels of tumor necrosis factor α (TNF-α), albumin, and interleukin 6 (IL-6). Histological analysis of the spleen, lungs, kidneys, and liver was performed in mice receiving 10 mg/kg SBCoV207 or control treatment.

A 24-hour intranasal biodistribution study was performed using blood and urine samples that were collected prior to euthanasia at one, three, six, or 24 hours after SBCoV207 administration. Thereafter, intraperitoneal and intravenous biodistribution and safety studies were performed. Finally, the concentrations of SBCoV207 in different organ tissues were calculated.

Study Findings

SBCoV207 was found to inhibit viral infection and lead to a ten-fold reduction in viral messenger RNA (mRNA) levels compared to missense nanoligomers. SPR measurements indicated strong binding of SBCoV207 to the miR2392 binding sequence compared to the missense nanoligomers. However, none of the mice showed weight changes and continued to drink and eat normally after SBCoV207 administration.

Histological studies indicated alveolar hemorrhage in the lungs, along with subacute inflammation in the livers of SBCoV207-treated and control mice. Albumin, TNF-α, and IL-6 levels were normal in both treated and control mice. Furthermore, most chemokine and cytokine levels were below the limit of detection (LOD), even 24 hours after SBCoV207 administration.

The highest levels of nanoligomers were found in the kidneys, urine, lungs, and whole blood. SBCoV207 was eliminated via urinary excretion several hours after administration and showed low accumulation in organs at five days, regardless of the route of administration. In particular, no toxicity was observed at any time from one hour to five days after administration.

Steady-state concentration of SBCoV207 was achieved in the spleen and liver via the intraperitoneal and intravenous routes. Between 500 and 700 ng/g of SBCoV207 tissue were observed after five days in liver, urine, and spleen, while even lower concentrations were reported in other organ tissues. Furthermore, two mice showed elevated levels of SBCoV207 in the lungs and one in the kidney five days after administration.

Conclusions

The current study determined that SBCoV207 nanoligomer treatment showed no toxicity in mice, regardless of their routes of administration. SBCoV207 exhibited a high biodistribution in the lungs and the site of infection; however, its accumulation in organs was found to be low.

Taken together, nanoligomer treatment has the potential to be effective and safe for treating severe COVID-19, especially in areas with low vaccination rates or where new variants have been detected. This approach can also help provide a strategy to mitigate future pandemics.[if–>

Journal reference:

  • McCollum, C. R., Courtney, C. M., O’Connor, N. J., et al. (2022). Nanoligomers Targeting Human miRNA for the Treatment of Severe COVID-19 Are Safe and Nontoxic in Mice. ACS Biomaterials Science & Engineering. doi:10.1021/acsbiomaterials.2c00510.
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