McDonagh P, Sheehy PS, Norris JM. Combination siRNA therapy against feline coronavirus can delay the emergence of antiviral resistance in vitro. Vet Microbiol. 2015 Mar 23;176(1-2):10-18.
Feline infectious peritonitis (FIP), caused by a feline corona virus, continues to be a leading cause of death in cats, in particular, young cats. Although, the fairly benign feline enteric corona virus is actually quite common in the cat population, in a small subset of genetically predisposed cats, FIP may develop after the virus gains enhanced and sustained replication in cells (i.e., monocytes and macrophages) beyond the gastrointestinal tract.
Immunomodulatory and immunosuppressive drugs have been the mainstay of treatment for affected cats; however, controlled studies show little benefit. Since HIV/AIDS appeared on the scene, a large number of antiviral therapies have benefited this population of people. On the other hand, antiviral therapy for FIP affect cats has received little clinical attention and may similar benefit.
Researchers from University of Sydney, Sydney, Australia have previously demonstrated effective in vitro inhibition of FIPV using small-interfering RNA (siRNA). One of the major challenges with any antiviral therapeutic is viral drug resistance, which may develop during treatment, or be pre-existing in a viral population. Since siRNA are exquisitely RNA sequence specific for disrupting viral replication, single viral nucleotide mutations can greatly decrease siRNA efficacy. In addition, corona viruses, such as FIP, have a high mutation rate, making viral drug resistance development very likely.
This project addressed siRNA mediated inhibition of FIP virus by looking at combinations siRNA therapy targeting previously identified highly effective anti-FIP activity against virulent FIP1146 FIP virus strain. The authors designed three traditional types of siRNAs and two Dicer-substrate siRNAs. Dicer-substrate siRNAs have been shown to be more efficacious than the more traditional type of siRNAs. The ability to prevent viral mutation (viral escape) and develop drug resistance was investigated by serial passage through cells treated with one, two or three siRNA agents simultaneously.
Combination therapy with three traditional siRNA agents prevented viral escape over five passages. Dual Dicer-substrate siRNA also showed potent antiviral effects. In conclusion, combination siRNA therapy, in particular using Dicer-substrate siRNAs, shows promise for future investigation of in vivo use to treat FIP affected cats. [GO]
Anis EA, Wilkes RP, Kania SA, Legendre AM, Kennedy MA. Effect of small interfering RNAs on in vitro replication and gene expression of feline coronavirus. Am J Vet Res. 2014 Sep;75(9):828-34.
Kim Y, Shivanna V, et al. Broad-spectrum inhibitors against 3C-like proteases of feline coronaviruses and feline caliciviruses. J Virol. 2015 May;89(9):4942-50.
feline infectious peritonitis