The lack of antiviral treatments for respiratory infections became evident with the emergence and worldwide spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Study: Nanoligomers Targeting Human miRNA for the Treatment of Severe COVID-19 Are Safe and Nontoxic in Mice. Image Credit: cherezoff / Shutterstock.com
Background
SARS-CoV-2 is a positive-stranded enveloped ribonucleic acid (RNA) virus that binds to the human receptor angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane protease receptor serine 2 (TMPRSS2), both of which are primarily located 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 harm the liver, cardiovascular system, kidneys, gastrointestinal tract, and nervous system.
Although several vaccines have been developed against SARS-CoV-2, the continuous emergence of new variants, lack of vaccine availability, and/or low vaccination rates continue to threaten the safety of the global population against COVID-19. In addition to the high fatality rates of COVID-19, the potential long-term effects that have been reported in individuals who have recovered from the disease are also a considerable public health concern.
Antisense oligonucleotides (ASOs) are single-stranded synthetic nucleotides that can bind to organic nucleic acids and molecules such as synthetic small interfering RNAs (siRNAs), peptide nucleic acids (PNAs), and morpholinos.
PNAs consist of nucleobases on a pseudo-peptide backbone and have a long in vivo half-life. Furthermore, PNAs can strongly bind to both RNA and DNA due to an uncharged backbone and thus can be used as inhibitory therapeutics that binds much more tightly to their target as compared to DNA-based technologies.
Micro-RNAs (miRNAs) are non-coding small RNAs that serve many functions, including the post-transcriptional regulation of genes that are associated with infections. High levels of miRNA 2392 (miR-2392) have been observed in humans as a result of severe SARS-CoV-2 infection.
Moreover, miR-2392 has also been reported to help in viral replication and limit the host immune response to SARS-Cov-2. Hypoxia, upregulation of inflammation, glycolysis, and mitochondrial suppression have also been observed with high levels of miR-2392.
Previous studies have reported that PNAs can bind miRNAs and modulate immune responses, detect biomarkers, fight tumors, or serve as bio-supramolecular tags. However, the use of antisense technologies has several challenges, as nucleic acids require a delivery vehicle to be able to pass into cells.
One approach to overcome this challenge can be the use of nanoligomers. Nanoligomers contain gold nanoparticles that improve their transport and distribution throughout the body.
Previous studies with nanoligomers have indicated lower SARS-CoV-2 tiers, as well as no toxicity, thus making them a suitable treatment option. However, further knowledge is required on their in vivo biodistribution, safety, and pharmacokinetics (PK).
A new ACS Biomaterials Science & Engineering study discusses the biodistribution and safety of a novel nanoligomer referred to as SBCoV207, which was used to target miR-2392 in a murine 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 in Vero E6 cells. This was followed by a quantitative reverse-transcription polymerase chain reaction (PCR) assay for measurement of SARS-CoV-2 RNA levels, as well as immunofluorescence of the viral nucleocapsid (N) protein.
A five-day intranasal safety study was carried out using female BALB/c mice that were between eight to 12 weeks of age. SBCoV207 doses of 1, 2, 5, or 10 mg/kg were administered to each group intranasally and monitored for five days before being euthanized.
Blood and urine samples were collected before euthanasia, while tissue samples were collected thereafter. 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 conducted on mice that received either 10 mg/kg of SBCoV207 or the control treatment.
A 24-hour intranasal biodistribution study was carried out using blood and urine samples that were collected before euthanasia at one, three, six, or 24 hours after SBCoV207 administration. Thereafter, intraperitoneal as well as intravenous safety and biodistribution studies were conducted. Finally, the SBCoV207 concentrations in different organ tissues were calculated.
Study findings
SBCoV207 was found to inhibit viral infection, as well as lead to a ten-fold reduction of viral messenger RNA (mRNA) levels as compared to missense nanoligomers. SPR measurements indicated strong binding of SBCoV207 to the miR2392 binding sequence as compared to missense nanoligomers. However, none of the mice exhibited weight change and continued to drink and eat normally following administration of SBCoV207.
Histological studies indicated alveolar hemorrhage in the lungs, along with subacute inflammation in the livers of both SBCoV207-treated and control mice. Albumin, TNF-α, and IL-6 levels were normal in both treated and control mice. Moreover, most chemokine and cytokine levels were below the limit of detection (LOD), even 24 hours post-SBCoV207 administration.
The highest levels of nanoligomers were found in the kidneys, urine, lungs, and whole blood. SBCoV207 was eliminated through urinary excretion within several hours of administration and exhibited low accumulation in organs by five days, irrespective of the route of administration. Notably, no toxicity was observed at any time from one hour to five days post-administration.
The steady-state concentration of SBCoV207 was achieved in the spleen and liver through the intraperitoneal and intravenous routes. Between 500-700 ng/g tissue of SBCoV207 was observed after five days in the liver, urine, and spleen, while even lower concentrations were reported in other organ tissues. Additionally, two mice showed high SBCoV207 levels in the lungs and one in the kidney five days post-administration.
Conclusions
The current study determined that the nanoligomer treatment SBCoV207 showed no toxicity in mice, irrespective of their administration routes. SBCoV207 exhibited high biodistribution in the lungs and infection site; however, its accumulation in organs was observed to be low.
Taken together, nanoligomer treatment has the potential to be effective and safe for treating severe COVID-19, especially in areas of low vaccination rates or where new variants have been detected. This approach can also help provide a strategy for mitigating future pandemics.
- 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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