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Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):1864-9. doi: 10.1073/pnas.0910603106. Epub 2010 Jan 11.

Lipid-like materials for low-dose, in vivo gene silencing.

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1
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Erratum in

  • Proc Natl Acad Sci U S A. 2010 May 25;107(21):9915.

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.

PMID:
20080679
PMCID:
PMC2804742
DOI:
10.1073/pnas.0910603106
[Indexed for MEDLINE]
Free PMC Article

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