Abstract

We report rapid, potent reversal of GalNAc-siRNA-mediated RNA interference (RNAi) activity in vivo with short, synthetic, high-affinity oligonucleotides complementary to the siRNA guide strand. We found that 9-mers with five locked nucleic acids (LNAs) have the highest potency across several targets. Our modular, sequence-specific approach, named REVERSIR, may enhance the therapeutic profile of any long-acting GalNAc–siRNA (short interfering RNA) conjugate by enabling control of RNAi pharmacology.

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Acknowledgements

We thank J. Maraganore, R. Meyers, K. Charisse, and K. Fitzgerald for helpful discussions. We thank J. Barry for help with RNA-seq.

Author information

Affiliations

  1. Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.

    • Ivan Zlatev
    • , Adam Castoreno
    • , Christopher R Brown
    • , June Qin
    • , Scott Waldron
    • , Mark K Schlegel
    • , Rohan Degaonkar
    • , Svetlana Shulga-Morskaya
    • , Huilei Xu
    • , Swati Gupta
    • , Shigeo Matsuda
    • , Akin Akinc
    • , Kallanthottathil G Rajeev
    • , Muthiah Manoharan
    • , Martin A Maier
    •  & Vasant Jadhav

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Contributions

I.Z., A.C., M.M., A.A., K.G.R., M.A.M., and V.J. designed the research. I.Z., S.W., and M.K.S. synthesized oligonucleotides and generated Tm data. A.C. generated in vitro data in PMHs. J.Q. generated in vivo data. R.D. and S.G. generated ASGPR binding and uptake data. C.R.B. quantified siRNA levels and REVERSIR association with Ago2. S.S.-M. generated and H.X. analyzed RNA-seq data. S.M. contributed reagents. I.Z. and V.J. wrote the manuscript with input from all authors.

Competing interests

All authors are or were employees of Alnylam Pharmaceuticals when they contributed to this work. REVERSIR is a trademark of Alnylam Pharmaceuticals.

Corresponding author

Correspondence to Vasant Jadhav.

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