Robust and durable prophylactic protection conferred by RNA interference in preclinical models of SARS-CoV-2
Yesseinia I Anglero-Rodriguez; Florian A Lempp; James McIninch; Mark K Schlegel; Christopher R Brown; Donald J Foster; Adam B Castoreno; Tuyen Nguyen; Megha Subramanian; Martin Montiel-Ruiz; Hannah Kaiser; Anna Sahakyan; Roberto Spreafico; Svetlana Shulga Morskaya; Joseph D Barry; Daniel Berman; Stephanie Lefebvre; Anne Kasper; Timothy Racie; Diann Weddle; Melissa Mobley; Arlin Rogers; Joseph Dybowski; Saheo Chong; Jayprakash Nair; Amy Simon; Kevin Sloan; Seungmin Hwang; Herbert W Virgin; Kevin Fitzgerald; Martin A Maier; Gregory Hinkle; Christy Hebner; Akin Akinc; Vasant Jadhav.
Preprint
en Inglés
| PREPRINT-BIORXIV | ID: ppbiorxiv-485044
RNA interference is a natural antiviral mechanism that could be harnessed to combat SARS-CoV-2 infection by targeting and destroying the viral genome. We screened lipophilic small-interfering RNA (siRNA) conjugates targeting highly conserved regions of the SARS-CoV-2 genome and identified leads targeting outside of the spike-encoding region capable of achieving [≥]3-log viral reduction. Serial passaging studies demonstrated that a two-siRNA combination prevented development of resistance compared to a single-siRNA approach. A two-siRNA combination delivered intranasally protected Syrian hamsters from weight loss and lung pathology by viral infection upon prophylactic administration but not following onset of infection. Together, the data support potential utility of RNAi as a prophylactic approach to limit SARS-CoV-2 infection that may help combat emergent variants, complement existing interventions, or protect populations where vaccines are less effective. Most importantly, this strategy has implications for developing medicines that may be valuable in protecting against future coronavirus pandemics.
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