title: Characterization of antisense oligonucleotides comprising 2'-deoxy-2'-fluoro-beta-D-arabinonucleic acid (FANA): specificity, potency, and duration of activity.
abstract: Antisense oligonucleotides (AON) are being developed for a wide array of therapeutic applications. Significant improvements in their serum stability, target affinity, and safety profile have been achieved with the development of chemically modified oligonucleotides. Here, we compared 2'-deoxy-2'-fluoro-beta-D-arabinonucleic acid (FANA)-containing AONs with phosphorothioate oligodeoxynucleotides (PS-DNA), 2'-O-methyl-RNA/DNA chimeras and short interfering RNAs (siRNA) with respect to their target knockdown efficacy, duration of action and resistance to nuclease degradation. Results show that two different configurations of FANA/DNA chimeras (altimers and gapmers) were found to have potent antisense activity. Specific target inhibition was observed with both FANA configurations with an estimated EC50 value comparable to that of an siRNA but 20-to 100-fold lower than the other commonly used AONs. Moreover, the FANA/DNA chimeras showed increased serum stability that was correlated with sustained antisense activity for up to 4 days. Taken together, these results indicate that chimeric FANA/DNA AONs are promising new tools for therapeutic gene silencing when increased potency and duration of action are required.
authors.affiliation: Topigen Pharmaceuticals Inc., Montreal, Quebec, Canada.
authors.forename: Nicolay
authors.initials: N
authors.lastname: Ferrari
authors.forename: Denis
authors.initials: D
authors.lastname: Bergeron
authors.forename: Anna-Lisa
authors.initials: AL
authors.lastname: Tedeschi
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mangos
authors.forename: Luc
authors.initials: L
authors.lastname: Paquet
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Renzi
authors.forename: Masad J
authors.initials: MJ
authors.lastname: Damha
mesh_terms: D001088:Arabinonucleotides / Q000494:pharmacology*; D004355:Drug Stability; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008156:Luciferases / Q000037:antagonists & inhibitors / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000737:chemistry* / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors
chemical_list: C507672:2'-deoxy-2'-fluoro-beta-D-arabinonucleic acid; D001088:Arabinonucleotides; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; D013873:Thionucleotides; D008156:Luciferases