Author:
Love Kevin T.,Mahon Kerry P.,Levins Christopher G.,Whitehead Kathryn A.,Querbes William,Dorkin J. Robert,Qin June,Cantley William,Qin Liu Liang,Racie Timothy,Frank-Kamenetsky Maria,Yip Ka Ning,Alvarez Rene,Sah Dinah W. Y.,de Fougerolles Antonin,Fitzgerald Kevin,Koteliansky Victor,Akinc Akin,Langer Robert,Anderson Daniel G.
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.
Publisher
Proceedings of the National Academy of Sciences
Cited by
747 articles.
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