Inhibition of respiratory syncytial virus infections with morpholino oligomers in cell cultures and in mice

被引:45
作者
Lai, Shen-Hao [1 ,2 ,3 ]
Stein, David A. [4 ]
Guerrero-Plata, Antonieta [1 ]
Liao, Sui-Ling [1 ,2 ,3 ]
Ivanciuc, Teodora [1 ]
Hong, Chao [1 ]
Iversen, Patrick L. [4 ]
Casola, Antonella [1 ,5 ,6 ]
Garofalo, Roberto P. [1 ,5 ,6 ]
机构
[1] Univ Texas Med Branch, Dept Pediat, Galveston, TX 77555 USA
[2] Chang Gung Childrens Hosp, Taoyuan Hsien, Taiwan
[3] Chang Gung Univ, Tao Yuan, Taiwan
[4] AVI BioPharma Inc, Corvallis, OR USA
[5] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA
[6] Univ Texas Med Branch, Sealy Ctr Vaccine Dev, Galveston, TX 77555 USA
关键词
D O I
10.1038/mt.2008.81
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
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 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.
引用
收藏
页码:1120 / 1128
页数:9
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