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- Title
Harnessing a physiologic mechanism for siRNA delivery with mimetic lipoprotein particles.
- Authors
Nakayama, Tomoko; Butler, James S; Sehgal, Alfica; Severgnini, Mariano; Racie, Tim; Sharman, Jennifer; Ding, Feng; Morskaya, Svetlana Shulga; Brodsky, Joshua; Tchangov, Lubomir; Kosovrasti, Verbena; Meys, Mike; Nechev, Lubomir; Wang, Gang; Peng, Chang Geng; Fang, Yupang; Maier, Martin; Rajeev, Kallanthottathil G; Li, Robert; Hettinger, Julia; Barros, Scott; Clausen, Valerie; Zhang, Xuemei; Wang, Qianfan; Hutabarat, Renta; Dokholyan, Nikolay V; Wolfrum, Christian; Manoharan, Muthiah; Kotelianski, Victor; Stoffel, Markus; Sah, Dinah Wy
- Abstract
Therapeutics based on RNA interference (RNAi) have emerged as a potential new class of drugs for treating human disease by silencing the target messenger RNA (mRNA), thereby reducing levels of the corresponding pathogenic protein. The major challenge for RNAi therapeutics is the development of safe delivery vehicles for small interfering RNAs (siRNAs). We previously showed that cholesterol-conjugated siRNAs (chol-siRNA) associate with plasma lipoprotein particles and distribute primarily to the liver after systemic administration to mice. We further demonstrated enhancement of silencing by administration of chol-siRNA pre-associated with isolated high-density lipoprotein (HDL) or low-density lipoprotein (LDL). In this study, we investigated mimetic lipoprotein particle prepared from recombinant apolipoprotein A1 (apoA) and apolipoprotein E3 (apoE) as a delivery vehicle for chol-siRNAs. We show that apoE-containing particle (E-lip) is highly effective in functional delivery of chol-siRNA to mouse liver. E-lip delivery was found to be considerably more potent than apoA-containing particle (A-lip). Furthermore, E-lip-mediated delivery was not significantly affected by high endogenous levels of plasma LDL. These results demonstrate that E-lip has substantial potential as delivery vehicles for lipophilic conjugates of siRNAs.
- Publication
Molecular therapy : the journal of the American Society of Gene Therapy, 2012, Vol 20, Issue 8, p1582
- ISSN
1525-0024
- Publication type
Journal Article
- DOI
10.1038/mt.2012.33