Lipid-like Materials for Low-dose, in Vivo Gene Silencing

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Jan 19

PMID 20080679

Citations 387

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

Affiliations

Soon will be listed here.

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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