ABSTRACT
The continuous evolution of SARS-CoV-2 variants complicates efforts to combat the ongoing pandemic, underscoring the need for a dynamic platform for the rapid development of pan-viral variant therapeutics. Oligonucleotide therapeutics are enhancing the treatment of numerous diseases with unprecedented potency, duration of effect, and safety. Through the systematic screening of hundreds of oligonucleotide sequences, we identified fully chemically stabilized siRNAs and ASOs that target regions of the SARS-CoV-2 genome conserved in all variants of concern, including delta and omicron. We successively evaluated candidates in cellular reporter assays, followed by viral inhibition in cell culture, with eventual testing of leads for in vivo antiviral activity in the lung. Previous attempts to deliver therapeutic oligonucleotides to the lung have met with only modest success. Here, we report the development of a platform for identifying and generating potent, chemically modified multimeric siRNAs bioavailable in the lung after local intranasal and intratracheal delivery. The optimized divalent siRNAs showed robust antiviral activity in human cells and mouse models of SARS-CoV-2 infection and represent a new paradigm for antiviral therapeutic development for current and future pandemics.
Subject(s)
COVID-19 , Humans , Animals , Mice , RNA, Small Interfering/genetics , COVID-19/therapy , SARS-CoV-2/genetics , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Oligonucleotides , LungABSTRACT
This case study describes the process of selecting the most appropriate state-wide hospital system to manage COVID-19 cases in a setting of low community transmission of COVID-19 infection. A rapid review of the literature was conducted of the advantages and disadvantages of having designated COVID hospitals. This led to three different options being presented for discussion. Following consultation, the option chosen was for all hospital facilities to remain prepared to care for COVID-19 patients where they present rather than having specified designated hospitals because this was considered the most practical option currently.