Single therapeutic dose of an antiviral UL29 siRNA swarm diminishes symptoms and viral load of mice infected intranasally with HSV‐1

Abstract Herpes simplex virus type 1 (HSV‐1) is a human pathogen that causes recurrent infections. Acyclovir‐resistant strains exist and can cause severe complications, which are potentially untreatable with current therapies. We have developed siRNA swarms that target a 653 base pair long region of the essential HSV gene UL29. As per our previous results, the anti‐UL29 siRNA swarm effectively inhibits the replication of circulating HSV strains and acyclovir‐resistant HSV strains in vitro, while displaying a good safety profile. We investigated a single intranasal therapeutic dose of a siRNA swarm in mice, which were first inoculated intranasally with HSV‐1 and given treatment 4 h later. We utilized a luciferase‐expressing HSV‐1 strain, which enabled daily follow‐up of infection with in vivo imaging. Our results show that a single dose of a UL29‐targeted siRNA swarm can inhibit the replication of HSV‐1 in orofacial tissue, which was reflected in ex vivo HSV titers and HSV DNA copy numbers as well as by a decrease in a luciferase‐derived signal. Furthermore, the treatment had a tendency to protect mice from severe clinical symptoms and delay the onset of the symptoms. These results support the development of antiviral siRNA swarms as a novel treatment for HSV‐1 infections.