Inhibition of respiratory syncytial virus infections with morpholino oligomers in cell cultures and in mice.
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 to prevent RSV infection, and the available therapeutic agents are of limited utility. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) 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 PPMOs, designed to target sequence that includes the 5'-terminal region and translation start-site region of RSV L mRNA, were tested for anti-RSV activity in cultures of two human-airway cell lines. Both PPMOs showed minimal cytotoxicity and one of them, (AUG-2), reduced viral titers by >2.0 log(10). Intranasal (i.n.) treatment of BALB/c mice with AUG-2 PPMO before the RSV inoculation produced a reduction in viral titer of 1.2 log(10) in lung tissue at day 5 postinfection (p.i.), and attenuated pulmonary inflammation at day 7 postinfection. These data show that the AUG-2 PPMO possesses potent anti-RSV activity and is worthy of further investigation as a candidate for potential therapeutic application.
Lai
Shen-Hao
SH
Department of Pediatrics, University of Texas Medical Branch at Galveston, Galveston, Texas 77555-0369, USA.
Stein
David A
DA
Guerrero-Plata
Antonieta
A
Liao
Sui-Ling
SL
Ivanciuc
Teodora
T
Hong
Chao
C
Iversen
Patrick L
PL
Casola
Antonella
A
Garofalo
Roberto P
RP
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003062:Codon; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008168:Lung / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D018075:RNA, Complementary / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018357:Respiratory Syncytial Virus Infections / Q000378:metabolism*
D003062:Codon; D018075:RNA, Complementary; D012333:RNA, Messenger