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The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs

Nature Nanotechnology volume 14, pages 1084–1087 (2019)Cite this article

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The regulatory approval of Onpattro, a lipid nanoparticle-based short interfering RNA drug for the treatment of polyneuropathies induced by hereditary transthyretin amyloidosis, paves the way for clinical development of many nucleic acid-based therapies enabled by nanoparticle delivery.

Nanomedicines resulting from the application of nanotechnology to medicine are having an increasing impact on the treatment of disease. This applies particularly to nanomedicines using lipid nanoparticle (LNP) drug delivery systems as there are now more than ten US Food and Drug Administration (FDA) approved pharmaceuticals employing LNPs to deliver drugs to disease sites (Table 1). Most of these nanomedicines are formulations of cancer drugs that offer the benefits of reduced toxicity and/or enhanced efficacy compared to the ‘free’ drug1. Due to the clinical success of LNP-based drug delivery systems, we now have a good understanding of the requirements for successful clinical translation of LNP systems for delivery of small molecules. Translational criteria include a size range of 100 nm or less, highly efficient encapsulation techniques, a low surface charge, robust, scalable manufacturing processes and adequate product stability2.

Table 1 LNP drugs that have received regulatory approval from the FDA or EMA
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Fig. 1: Integrated model of lipid nanoparticle (LNP)-mediated delivery of siRNA to hepatocytes in vivo.
Fig. 2: LNP siRNA systems containing 2nd generation ionizable aminolipids exhibit greatly improved potency for silencing factor VII (FVII) in the liver.
Fig. 3: Phase I clinical trials of ALN-TTR01 and ALN-TTR02 (patisiran).

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Authors and Affiliations

  1. Alnylam Pharmaceuticals, Cambridge, MA, USA

    Akin Akinc, Martin A. Maier, Muthiah Manoharan, Kevin Fitzgerald, Muthusamy Jayaraman & Scott Barros

  2. Acuitas Therapeutics, Vancouver, BC, Canada

    Steven Ansell, Xinyao Du, Michael J. Hope, Thomas D. Madden, Barbara L. Mui, Sean C. Semple & Ying K. Tam

  3. University of British Columbia, Vancouver, BC, Canada

    Marco Ciufolini, Dominik Witzigmann, Jayesh A. Kulkarni, Roy van der Meel & Pieter R. Cullis

  4. NanoMedicines Innovation Network, University of British Columbia, Vancouver, BC, Canada

    Pieter R. Cullis

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  1. Akin Akinc
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Correspondence to Pieter R. Cullis.

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Competing interests

A.A., M.A.M., M.M., K.F., M.J. and S.B. are employees of Alnylam Pharmaceuticals. S.A., X.D., M.J.H., T.D.M., B.L.M., S.C.S. and Y.K.T. are employees of Acuitas. P.R.C. has financial holdings in Acuitas.

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Akinc, A., Maier, M.A., Manoharan, M. et al. The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs. Nat. Nanotechnol. 14, 1084–1087 (2019). https://doi.org/10.1038/s41565-019-0591-y

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