INHIBITION OF RESPIRATORY SYNCYTIAL VIRUS INFECTION IN CELL CULTURES AND IN MICE WITH MORPHOLINO OLIGOMERS

摘要

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in infants, young children, and high-risk adults. Currently, there is no vaccine for the prevention of RSV infection, and available therapeutics are of limited utility. Peptide conjugated phosphorodiamidate morpholino oligomers (PPMO) are a class of antisense agents that can enter cells readily and interfere with viral protein expression through steric blocking of complementary RNA. Two antisense PPMO, designed to target sequence that includes the 5′ terminal- and translation start site-regions of RSV L mRNA, were tested for anti-RSV activity in cultures of two human airway cell lines. Both PPMO showed minimal cytotoxicity, and one of them (AUG-2), reduced viral titers by more than 2.0 log10. Intranasal treatment of BALB/c mice with AUG-2 PPMO prior to RSV inoculation produced a reduction in viral titer of 1.2 log10 in lung tissue at day 5 post-infection, and attenuated pulmonary inflammation at day 7 post-infection. These data show that the AUG-2 PPMO possessed potent anti-RSV activity and is worthy of further investigation as a candidate for therapeutic development.