Short antisense oligonucleotides with novel 2'-4' conformationaly restricted nucleoside analogues show improved potency without increased toxicity in animals.
The potency of second generation antisense oligonucleotides (ASOs) in animals was increased 3- to 5 -fold (ED(50) approximately 2-5 mg/kg) without producing hepatotoxicity, by reducing ASO length (20-mer to 14-mer) and by employing novel nucleoside modifications that combine structural elements of 2'-O-methoxyethyl residues and locked nucleic acid. The ability to achieve this level of potency without any formulation agents is remarkable and likely to have a significant impact on the future design of ASOs as therapeutic agents.
Seth
Punit P
PP
Isis Pharmaceuticals, 1891 Rutherford Road, Carlsbad, California 92008, USA. pseth@isisph.com
Siwkowski
Andrew
A
Allerson
Charles R
CR
Vasquez
Guillermo
G
Lee
Sam
S
Prakash
Thazha P
TP
Wancewicz
Edward V
EV
Witchell
Donna
D
Swayze
Eric E
EE
D000818:Animals; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009705:Nucleosides / Q000737:chemistry*; D016376:Oligonucleotides, Antisense / Q000737:chemistry* / Q000633:toxicity*; D051059:PTEN Phosphohydrolase / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects; D018675:Toxicity Tests
D009705:Nucleosides; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D051059:PTEN Phosphohydrolase