Lipid-like materials for low-dose,in vivo gene silencing |
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| Authors: | Kevin T. Love Kerry P. Mahon Christopher G. Levins Kathryn A. Whitehead William Querbes J. Robert Dorkin June Qin William Cantley Liu Liang Qin Timothy Racie Maria Frank-Kamenetsky Ka Ning Yip Rene Alvarez Dinah W. Y. Sah Antonin de Fougerolles Kevin Fitzgerald Victor Koteliansky Akin Akinc Robert Langer Daniel G. Anderson |
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| Affiliation: | aDepartment of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.;bDavid H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.;cDepartment of Anesthesiology, Division of Critical Care Medicine, Children’s Hospital, Harvard Medical School, Boston, MA 02115, and ;dAlnylam Pharmaceuticals, Inc., 300 Third Street, Cambridge, MA 02142, |
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| Abstract: | Significant effort has been applied to discover and develop vehicles which can guide small interfering RNAs (siRNA) through the many barriers guarding the interior of target cells. While studies have demonstrated the potential of gene silencing in vivo, improvements in delivery efficacy are required to fulfill the broadest potential of RNA interference therapeutics. Through the combinatorial synthesis and screening of a different class of materials, a formulation has been identified that enables siRNA-directed liver gene silencing in mice at doses below 0.01 mg/kg. This formulation was also shown to specifically inhibit expression of five hepatic genes simultaneously, after a single injection. The potential of this formulation was further validated in nonhuman primates, where high levels of knockdown of the clinically relevant gene transthyretin was observed at doses as low as 0.03 mg/kg. To our knowledge, this formulation facilitates gene silencing at orders-of-magnitude lower doses than required by any previously described siRNA liver delivery system. |
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| Keywords: | lipidoid siRNA delivery multiple gene silencing primates |
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