Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
Edited* by Alexander M. Klibanov, Massachusetts Institute of Technology, Cambridge, MA, and approved January 16, 2014 (received for review December 10, 2013)
Significance
The safe, selective, and efficient delivery of siRNA is a key challenge to the broad application of siRNA therapeutics in humans. Motivated by the structure of lipoproteins, we developed lipopeptide nanomaterials for siRNA delivery. In vivo in mice, siRNA–lipopeptide particles provide the most potent delivery to hepatocytes (ED50 ∼ 0.002 mg/kg for FVII silencing), with the highest selectivity of delivery to hepatocytes over nontarget cell types (orders of magnitude), yet reported. These materials also show efficacy in nonhuman primates.
Abstract
siRNA therapeutics have promise for the treatment of a wide range of genetic disorders. Motivated by lipoproteins, we report lipopeptide nanoparticles as potent and selective siRNA carriers with a wide therapeutic index. Lead material cKK-E12 showed potent silencing effects in mice (ED50 ∼ 0.002 mg/kg), rats (ED50 < 0.01 mg/kg), and nonhuman primates (over 95% silencing at 0.3 mg/kg). Apolipoprotein E plays a significant role in the potency of cKK-E12 both in vitro and in vivo. cKK-E12 was highly selective toward liver parenchymal cell in vivo, with orders of magnitude lower doses needed to silence in hepatocytes compared with endothelial cells and immune cells in different organs. Toxicity studies showed that cKK-E12 was well tolerated in rats at a dose of 1 mg/kg (over 100-fold higher than the ED50). To our knowledge, this is the most efficacious and selective nonviral siRNA delivery system for gene silencing in hepatocytes reported to date.
Footnotes
- ↵1To whom correspondence should be addressed. E-mail: dgander{at}mit.edu.
Author contributions: Y.D., R.L., and D.G.A. designed research; Y.D., K.T.L., J.R.D., S.S., Y.Z., D.C., R.L.B., H.Y., Y.C., A.J.V., C.A.A., G.S., K.T.O., W.W., A.S., A.K.R.L.-J., A.A., C.B., S.A.B., M.C., K.F., J.H., V. Kumar, T.I.N., J.Q., W.Q., and V. Kotelianski performed research; Y.D., K.T.L., J.R.D., S.S., Y.Z., D.C., R.L.B., H.Y., Y.C., A.J.V., C.A.A., G.S., K.T.O., W.W., A.S., A.K.R.L.-J., A.A., C.B., S.A.B., M.C., K.F., J.H., V. Kumar, T.I.N., J.Q., W.Q., V. Kotelianski, R.L., and D.G.A. analyzed data; and Y.D., K.T.L., A.J.V., C.A.A., D.J.S., R.L., and D.G.A. wrote the paper.
Conflict of interest statement: R.L. is a shareholder and member of the Scientific Advisory Board of Alnylam. D.G.A. is a consultant with Alnylam. R.L and D.G.A have sponsored research grants from Alnylam. Alnylam also has a license to certain intellectual property invented at Massachusetts Institute of Technology. A.A., S.A.B., M.C., K.F., J.H., V. Kumar, J.Q., and W.Q. are employed by Alnylam.
↵*This Direct Submission article had a prearranged editor.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1322937111/-/DCSupplemental.
Freely available online through the PNAS open access option.
Lipopeptides and selective siRNA delivery
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