| 摘要 |
The present invention is based, at least in part, upon the insight that compound DsiRNA agents can be generated using site-specific RNase H-cleavable double stranded nucleic acid double stranded nucleic acid regions to attach, e.g., one DsiRNA moiety to another DsiRNA moiety and/or one DsiRNA moiety to a functional group and/or payload. Because such double stranded nucleic acid joining sequences are site-specifically RNase H-cleavable, the bifunctional molecule is cleaved into DsiRNAs which bear terminal ends that orient dicer cleavage. The detrimental impact of administering a single double stranded nucleic acid RNAi agent of longer than 30-35 nucleotides in length (e.g., provocation of interferon response) can be minimized, as once administered or delivered to a subject or RNase H-containing cell, RNase H cleavage produces a shortened, active DsiRNA agent(s). The invention also provides bifunctional DsiRNA agents that are joined by double stranded DNA extension joining sequences—such bifunctional DsiRNA agents joined by dsDNA sequences do not provoke RNase H cleavage.
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