Targeted Therapy of Respiratory Syncytial Virus in African Green Monkeys by Intranasally Administered 2-5A Antisense

Abstract

Respiratory syncytial virus (RSV) is a leading cause of respiratory disease in infants, young children, immunocompromised patients, and the institutionalized elderly. Previous work had shown that RNase L, an antiviral enzyme of the interferon system, could be recruited to cleave RSV genomic RNA by attaching tetrameric 2prime prime or minute-5prime prime or minute-linked oligoadenylates (2-5A) to an oligonucleotide complementary to repetitive gene-start sequences within the RSV genome (2-5A antisense). A 2prime prime or minute-O-methyl RNA-modified analog of the lead 2-5A anti-RSV chimera is shown here to have enhanced antiviral activity in cell culture studies while also cleaving RSV genomic RNA in an RNase L- and sequence-specific manner. When administered intranasally to RSV-infected African green monkeys, this chimera reduced nasal RSV replication by up to four log(10) units in a dose- and time-dependent manner.

Viral Encounters with 2′,5′-Oligoadenylate Synthetase and RNase L during the Interferon Antiviral Response

“…In addition, expression of RNase L inhibitor (RLI) suppressed the IFN-␥ effect against RSV. The potential of RNase L activator drugs to block RSV infections was demonstrated by targeting RSV genomic RNA with 2-5A linked to an antisense oligonucleotide against the RSV repetitive-gene start site (60). The 2-5A antisense drug administered by the intranasal route to RSV-infected African green monkeys reduced viral yields by 4-log 10 units.…”

Animal Pneumoviruses: Molecular Genetics and Pathogenesis

“…Specific cleavage of hRSV genome RNA has been detected at antisense oligonucleotide binding sites (184). Because of the pattern of RNA cleavage observed, it was suggested that endogenous RNase H participated in hRSV (2) and, more recently, in vivo using an African green monkey model of hRSV infection (230). As of this writing, there are no publications describing antisense therapy in human clinical trials.…”

Antisense oligonucleotide-based therapeutics for cancer

“…RNase L is a ribonuclease activated by 2 0 -5 0 -linked oligoadenylates generated in response to interferon activation. Linkage of 2 0 -5 0 oligoadenylate to an antisense oligonucleotide has been reported to promote selective cleavage of the targeted mRNA (Torrence et al, 1993;Leaman et al, 2002).…”