Title : An unconventional therapeutic oligonucleotide effectively reduces SARS-CoV-2 RNA levels in preclinical animal studies
Abstract:
Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019, the number of confirmed cases worldwide exceeded 770 million in 222 countries by March 2024, with more than 7 million confirmed deaths, according to the statistics from the World Health Organization. In addition to quarantine measures, preventive measures, immunization of the population with vaccines, prophylaxis, symptomatic treatment, or secondary-use medications have become the main tools of prevention and therapeutic intervention against the virus.
Therapeutic oligonucleotides have attracted great interest due to their potency and potential to change the therapeutic landscape of many pathological conditions, including those of viral origin. Targeting the conserved SARS-CoV-2 RNA sequences essential for viral replication offers a rational approach to inhibiting viral infection and thereby halting disease progression.
Following the successful in vitro validation of a tailor-made therapeutic oligonucleotide with an unconventional structural design, called ASC1R, which was shown to be remarkably effective in transfected cell lines, we report here the results of subsequent preclinical animal studies of this active pharmaceutical substance. ASC1R has demonstrated excellent tolerability without any observed behavioural changes or mortality in acute and subacute toxicology studies in C57BL/6 mice, even at doses exceeding 100 times the therapeutically effective concentration. Functional studies showed effective reduction of target RdRp RNA levels in the liver of transfected mice by 95.1 (median (N=9), Q25-Q75=77.7-97.5) and 98.1% (median (N=9), Q25-Q75=94.1-98.8) after single application of ASC1R at doses of 1 and 10 mg/kg, respectively.
The therapeutic potential of ASC1R could translate into substantial clinical benefits for patients with COVID-19. Furthermore, in the context of infectious diseases, our results provide implications for the research and development of analogous antivirals for other diseases of viral origin. The findings could help meet the global challenge of developing new and safe treatment modalities.
This work was supported by the Slovak Research and Development Agency under Contracts No. PP-COVID-20-0007 and APVV-21-0220
