Targeted Therapy of Respiratory Syncytial Virus by 2-5a Antisense

Abstract

Respiratory syncytial virus is a leading cause of respiratory disease in infants, young children, immunocompromized patients, and the elderly. Previous work has shown that RNase L, an antiviral enzyme of the interferon system, can be recruited to cleave RSVgenomic RNA by attaching tetrameric 2' 5'-linked oligoadenylates (2 5A) to an antisense oligonucleotide complementary to repetitive intergenic sequences within the RSV genome (2 5A antisense). RBI034, a 2'-O-methyl RNA-modified analogue of the 2 5A anti-RSV compound, was found to have enhanced antiviral activity in cell culture studies while also cleaving RSV genomic RNA in an RNase L- and sequence-specific manner. RBI034s efficacy in suppressing RSV replication in cell culture is 50 to 100 times better than ribavirin, the only approved drug for RSV infection. Here we show that the activity of 2 SA antisense compound can be further enhanced by a combination treatment with interferon or ribavirin. The anti-RSV activity resulting from combination treatment is more potent than either treatment alone. We also demonstrate that RBI034 is effective against RSV in three different species: mice, cotton rats, and African green monkeys.

Antisense approaches for inhibiting respiratory syncytial virus

“…RBI034 was also effective in reducing viral titres in cotton rats when delivered by aerosol for 15 min/day using a reservoir concentration of 50 mg/ml in water (Figure 9). Similar results were found for RBI245 [128]. In comparison, cotton rats need to be treated for a minimum of 2 h a day with ribavirin at such concentrations to be effective [130][131][132][133].…”

“…Combination treatment of IFN and RBI245 at low concentrations also demonstrated synergistic protection against RSV infection in cell culture (Figure 6). RBI034 and RBI245 were found to be effective in reducing RSV infections in three different animal models [128]. RBI245 reduced viral titres from > 2000 to ∼ 100 plaque-forming units in mice when RBI245 was given intranasally at a concentration of 10 mg/kg every other day on days 1, 3 and 5 after, and once 6 h before RSV infection (Figure 7).…”

“…However, recent studies at Ridgeway Biosystems, Inc. have found 2-5A antisense compounds RBI034 and RBI245 to be effective anti-RSV agents suitable for clinical evaluation. Activity was demonstrated in three species using different routes of administration [117,128]. No toxicity was apparent.…”

Pharmacokinetics-Pharmacodynamics of a Respiratory Syncytial Virus Fusion Inhibitor in the Cotton Rat Model

“…However, no single animal model presents the complete spectrum of the disease observed in humans. Several primate models have been successfully used to demonstrate the prophylactic or therapeutic efficacy of human RSV antivirals (8,9,14,17). Small-rodent models of human RSV infection such as BALB/c mice and cotton rats (Sigmodon hispidus) have not only contributed to the understanding of the pathogenesis and immunobiology of human RSV disease but have also been used to demonstrate the in vivo efficacy of antiviral agents (1,7,10,13,14,19,20,27,28).…”

Treatment With Antisense Oligonucleotide Reduces the Expression of Type I Collagen in a Human-Skin Organ-Wound Model

“…Despite concerns about nonspecific effects, however, ASOs have very acceptable toxicity profiles. 27,30,31 ASOs are now being widely evaluated for the treatment of many diseases, including muscular dystrophy, 32 hypertension, 30,33 viral infections, 34 and cancer. 27,31 Previous studies have shown that ASOs to different collagen subtypes have been successful in reducing the expression of the targeted mRNA in different cell lines.…”