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Lipopeptide nanoparticles (LPNs) for potent in vivo delivery of siRNA selectively to hepatocytes

Rodent and nonhuman primate studies suggest LPNs could be used to deliver siRNAs selectively to hepatocytes. Synthetic lipoamino acid derivatives formulated in nanoparticles with siRNA were screened in mice for target gene knockdown in the liver, yielding a lead LPN containing a dilysine-derived diketopiperazine core and four amino acid, alcohol-based lipid tails. In mice, siRNAs targeting three widely expressed genes delivered with the lead LPN led to selective gene silencing in hepatocytes. In nonhuman primates, i.v. injection of siRNA targeting transthyretin (TTR) formulated in the lead LPN led to knockdown of TTR mRNA with an ED50 of ~0.002 mg/kg. Next steps could include further elucidating the mechanism of LPN uptake by hepatocytes.

SciBX 7(8); doi:10.1038/scibx.2014.239
Published online Feb. 27, 2014

Patent filed; available for licensing from Alnylam Pharmaceuticals Inc.

Dong, Y. et al. Proc. Natl. Acad. Sci. USA; published online Feb. 10, 2014;
Contact: Daniel G. Anderson, Massachusetts Institute of Technology, Cambridge, Mass.