Antisense treatments for biothreat agents.
Antisense oligomers (ASOs) represent a promising technology to treat viral and bacterial infections, and have already been shown to be successful against a variety of pathogens in cell culture studies and nonhuman primate models of infection. For these reasons, antisense technologies are being pursued as treatments against biothreat agents such as Ebola virus, dengue virus and Bacillus anthracis. Several generations of modified oligonucleotides have been developed to maximize nuclease resistance, target affinity, potency, cell entry, and other pharmacokinetic properties. First-generation ASOs contain phosphorothioate modifications to increase stability through nuclease resistance. Further chemical modifications in second-generation ASOs include 2'-O-methyl and 2'-O-methoxy-ethyl oligos, which increase nuclease resistance and oligo:RNA binding affinities. Third-generation ASOs contain a variety of chemical modifications that enhance stability, affinity and bioavailability. A fourth class of oligonucleotide-based compounds consists of small interfering RNAs, which have recently become widely used for gene knockdown in vitro and in vivo. This review focuses on the third-generation phosphorodiamidate morpholino oligomers, which are nonionic and contain a morpholine ring instead of a ribose, as well as phosphorodiamidate linkages in place of phosphorothioates. Multiple antisense oligomer-based therapeutics are being developed for use against biothreat agents, and antisense drugs will likely become a critical member of our arsenal in the defense against highly pathogenic, emerging or genetically engineered pathogens.
Warfield
Kelly L
KL
U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA.
Panchal
Rekha G
RG
Aman
M Javad
MJ
Bavari
Sina
S
D000818:Animals; D023482:Bioterrorism / Q000517:prevention & control*; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000145:classification / Q000493:pharmacokinetics / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000235:genetics
D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering