17 May, 2018 Nonclinical Research Published in Nature Biotechnology Describing REVERSIR Platform for Potent and Rapid Reversal of siRNA Activity for Tailored Control of RNAi Pharmacology
One of the main features of our ESC GalNAc-siRNA conjugates platform is potent and durable target knockdown in the liver sustained for several months in humans. In some cases, RNAi therapeutics may benefit from a technology that enables reversal of target mRNA knockdown and provides finer control over pharmacology, a desired attribute for therapeutic entities. REVERSIRTM molecules are GalNAc-conjugated, short, single-stranded, high affinity oligonucleotide constructs designed to recognize and bind to the complementary, RISC-bound antisense strand of siRNAs, thereby leading to rapid and complete reversal of RNAi-mediated target gene silencing activity in vivo.
The work described here led to the development of Alnylam’s REVERSIR platform with novel design features, including length dependence and positioning of high affinity modifications such as locked nucleic acids (LNA). Specifically, we found that 9-mers with five LNAs have the highest potency across several targets. Our studies provide comprehensive learnings applicable to other oligonucleotide therapeutics, such as anti-micro RNAs (anti-miRs). This modular, sequence-specific approach could prove therapeutically beneficial in providing finer control over the duration of action of GalNAc-siRNAs, particularly in the context of acute indications.