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Oligo MeetingWell, even as the carnage continues in the market, there's going to be the annual Oligonucleotide Therapeutics meeting next week. The abstracts are up at the link below. Alnylam has a couple interesting ones that I've re-posted below. https://dl.dropboxusercontent.com/u/106247711/OTS_2015_alcdesign_DropBox/2015OTS_Progam_Book_ABSTRACTS.pdf Reversirs for Rapid and Potent Reversal of siRNA Silencing Activity siRNA-GalNAc conjugates are emerging as a potential new class of medicine supporting a broad clinical pipeline across multiple therapeutic areas. We have been able to continuously optimize the siRNA design resulting in the Enhanced Stabilization Chemistry (ESC) platform exhibiting improved efficacy and extended duration lasting for several months. Here, we present the design and evaluation of compounds termed “Reversirs” that allow rapid and potent reversal of silencing activity. The proposed mechanism of action involves ASGPRmediated delivery of the “Reversir” followed by binding to the RISC-loaded antisense strand of siRNA to block target silencing. Through optimization of critical design features, such as size, metabolic stability and binding affinity, full reversal of silencing activity can potentially be achieved following administration of a single Reversir dose. Bis-siRNA Conjugates for Simultaneous Silencing of Two Transcripts siRNAs covalently conjugated to synthetic multivalent N-acetylgalactosamine (GalNAc) ligands represent a promising new class of RNAi therapeutics with demonstrated human proof-of-concept across multiple clinical programs. Simultaneous silencing of two different targets could result in superior therapeutic benefit e.g. in the case of an antiviral therapy it could result in reduced viral resistance. Here we present the design and evaluation of siRNA conjugates capable of silencing two different transcripts as a single chemical entity, termed “bis-siRNAs”. This approach ensures that cells receive both siRNAs simultaneously and with the same efficiency thereby maximizing the therapeutic benefit of dual target silencing. Multiple designs were evaluated and critical design parameters, such as placement of the ligand (terminal/internal) and the nature of the linker (cleavable/non-cleavable, nucleosidic/non-nucleosidic) between the siRNAs, were identified. Through optimization of those features robust in vivo activity, comparable to a cocktail of individual siRNA conjugates, was achieved. |
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