MIXED-BACKBONE OLIGONUCLEOTIDES AS SECOND GENERATION ANTISENSE OLIGONUCLEOTIDES - IN-VITRO AND IN-VIVO STUDIES

Antisense oligonucleotides are being evaluated in clinical trials as n ovel therapeutic agents. To further improve the properties of antisens e oligonucleotides, we have designed mixed-backbone oligonucleotides ( MBOs) Bat contain phosphorothioate segments at the 3' and 5' ends and have a modified oligodeoxynucleotide or oligoribonucleotide segment lo cated in the central portion of the oligonucleotide. Some of these MBO s indicate improved properties compared with phosphorothioate oligodeo xynucleotides with respect to affinity to RNA, RNase H activation, and anti-HIV activity. In addition, more acceptable pharmacological, in v ivo degradation and pharmacokinetic profiles were obtained with these MBOs.