Fully 2‘-Modified Oligonucleotide Duplexes with Improved in Vitro Potency and Stability Compared to Unmodified Small Interfering RNA
Charles Allerson(Ionis Pharmaceuticals (United States)), Namir Sioufi(Ionis Pharmaceuticals (United States)), Russell Jarres(Ionis Pharmaceuticals (United States)), Thazha P. Prakash(Ionis Pharmaceuticals (United States)), Nishant Naik(Ionis Pharmaceuticals (United States)), Andrés Berdeja(Ionis Pharmaceuticals (United States)), Lisa Wanders(Ionis Pharmaceuticals (United States)), Richard H. Griffey(Ionis Pharmaceuticals (United States)), Eric E. Swayze(Ionis Pharmaceuticals (United States)), Balkrishen Bhat(Ionis Pharmaceuticals (United States))
Cited by 440
Abstract
We have identified a small interfering RNA (siRNA) motif, consisting entirely of 2'-O-methyl and 2'-fluoro nucleotides, that displays enhanced plasma stability and increased in vitro potency. At one site, this motif showed remarkable >500-fold improvement in potency over the unmodified siRNA. This marks the first report of such a potent fully modified motif, which may represent a useful design for therapeutic oligonucleotides.