Nanoligomers Targeting Human miRNA for the Treatment of Severe COVID-19 Are Safe and Nontoxic in Mice

Abstract

The devastating effects of the coronavirus disease 2019 (COVID-19) pandemic have made clear a global necessity for antiviral strategies. Most fatalities associated with infection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) result at least partially from uncontrolled host immune response. Here, we use an antisense compound targeting a previously identified microRNA (miRNA) linked to severe cases of COVID-19. The compound binds specifically to the miRNA in question, miR-2392, which is produced by human cells in several disease states. The safety and biodistribution of this compound were tested in a mouse model via intranasal, intraperitoneal, and intravenous administration. The compound did not cause any toxic responses in mice based on measured parameters, including body weight, serum biomarkers for inflammation, and organ histopathology. No immunogenicity from the compound was observed with any administration route. Intranasal administration resulted in excellent and rapid biodistribution to the lungs, the main site of infection for SARS-CoV-2. Pharmacokinetic and biodistribution studies reveal delivery to different organs, including lungs, liver, kidneys, and spleen. The compound was largely cleared through the kidneys and excreted via the urine, with no accumulation observed in first-pass organs. The compound is concluded to be a safe potential antiviral treatment for COVID-19.

Screening Immunotherapy Targets to Counter Radiation-Induced Neuroinflammation

“…The Nanoligomer molecules not only cross the BBB, but also have low K D (dissociation constant), facilitating excellent therapeutic action even at low doses in vivo . 32 IP injection of GM-CSF downregulator showed Nanoligomer in the brain within 1 hour of injection (data not shown). Twenty-four hours post injection (hpi), Group 2 (vehicle) and group 3 (30D.443_CSF2) were exposed to a total dose of 3 Gy gamma total body irradiation (Fig.…”

“…48 Nanoligomer downregulators act either via targeting of mRNA to inhibit RNA stability and consequently protein expression or via targeting of DNA. 30,32 Nanoligomer upregulators trigger transcriptional activation by binding at the respective promoter region and attachment of specific domains that recruit transcriptional activators (Fig. 1B).…”

“…31 Nanoligomers offer improved stability, facile delivery and internalization, and superior target specificity compared to existing nucleic acid therapeutics. 32 In addition, they modulate related gene network targets ultimately resulting in pathway modulation. Previously, we have demonstrated that Nanoligomer technology is very effective in identifying lead targets and molecules for reversing radiation-induced immune dysfunction.…”

Identifying Optimal Neuroinflammation Treatment Using Nanoligomer™ Discovery Engine

“…56 Despite remarkable progress in the field of nucleic acid therapeutics based on microRNAs, small interfering RNAs, long non-coding RNAs, and deactivated CRISPR-Cas9 technology in the recent years, several challenges associated with their delivery, stability, internalization, and target specificity need to be addressed for their successful clinical translation and development as neuroinflammation countermeasures. [57][58][59] For example, technologies like deactivated CRISPR-Cas9 require tedious cloning and optimization that are time-consuming and expensive. Sachi has developed Nanoligomer TM neurotherapeutic discovery engine, a high-precision tool that generates sequence-specific, nano-biohybrid molecules called Nanoligomers TM to address the shortcomings of the existing methodologies.…”

“…60 Nanoligomers offer improved stability, facile delivery and internalization, high target specificity (on-target) and minimal off-targeting, and can be easily designed to rapidly create a library of neurotherapeutic molecules with the capability to cross the BBB using any route of administration (intraperitoneal IP, intranasal IN, or intravenous IV), superior biodistribution and minimal accumulation compared to existing nucleic acid therapeutics. 59 In addition, they modulate related gene network targets ultimately resulting in pathway modulation. Previously, we have demonstrated that Nanoligomer technology is very effective in identifying immunotherapy lead targets and molecules for countermeasure development.…”