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.

01 Mar 2004·Antiviral ResearchQ2 · MEDICINE

Potent inhibition of respiratory syncytial virus by combination treatment with 2–5A antisense and ribavirin

Q2 · MEDICINE

Article

Author: Hagen Cramer ; Mei Kuang ; Nilabh Chaudhary ; Zan Xu ; James R. Okicki

Respiratory syncytial virus (RSV) is a major cause of lower respiratory diseases in infants, young children, and the elderly. Ribavirin, the only currently approved drug for the treatment of RSV infections in the U.S., requires high doses to be effective. Therefore, it has only a limited clinical efficacy in the treatment of RSV infections. It has been shown that a cellular ribonuclease, RNase L, can be recruited by 2'-5' linked tetra-adenylates (2-5A) attached to an antisense sequence complementary to the RSV genome to specifically cleave RSV genomic RNA. Here we confirm the antiviral activity of the lead 2-5A antisense compound, RBI034, by using several different viral assays. We demonstrate that RBI034 is more efficient than antisense lacking 2-5A or small interfering dsRNA (siRNA) in inhibiting RSV replication. Although the best antiviral activity of RBI034 was observed with co-treatment of RSV infection, it remained effective even when administered 24 h after the initiation of infection. Interestingly, the activity of RBI034 can be further enhanced by a combination treatment with ribavirin. At suboptimal concentrations, neither ribavirin nor RBI034 was effective in suppressing RSV replication. However, a combination of these two drugs at the same suboptimal concentrations showed a potent inhibitory activity. The potent reduction of RSV replication by combination treatment was also confirmed in primary human airway epithelial cells. Therefore, a combination therapy of the 2-5A antisense compound RBI034 and ribavirin might be a more effective therapeutic approach for treating RSV infections than ribavirin alone.

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Indication	Highest Phase	Country/Location	Organization	Date
Respiratory Syncytial Virus Infections	Discovery	United States	Ridgeway Biosystems Inc.	-

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