Article abstract
Nature Biotechnology 26, 561 - 569 (2008)
Published online: 27 April 2008 | doi:10.1038/nbt1402
A combinatorial library of lipid-like materials for delivery of RNAi therapeutics
Akin Akinc1,2, Andreas Zumbuehl3,4, Michael Goldberg5, Elizaveta S Leshchiner3, Valentina Busini3, Naushad Hossain3, Sergio A Bacallado3, David N Nguyen3, Jason Fuller3, Rene Alvarez2, Anna Borodovsky2, Todd Borland2, Rainer Constien6,7, Antonin de Fougerolles2, J Robert Dorkin2, K Narayanannair Jayaprakash2, Muthusamy Jayaraman2, Matthias John6,7, Victor Koteliansky2, Muthiah Manoharan2, Lubomir Nechev2, June Qin2, Timothy Racie2, Denitza Raitcheva2, Kallanthottathil G Rajeev2, Dinah W Y Sah2, Jürgen Soutschek6,7, Ivanka Toudjarska2, Hans-Peter Vornlocher6,7, Tracy S Zimmermann2, Robert Langer1,3,5 & Daniel G Anderson1
Abstract
The safe and effective delivery of RNA interference (RNAi) therapeutics remains an important challenge for clinical development. The diversity of current delivery materials remains limited, in part because of their slow, multi-step syntheses. Here we describe a new class of lipid-like delivery molecules, termed lipidoids, as delivery agents for RNAi therapeutics. Chemical methods were developed to allow the rapid synthesis of a large library of over 1,200 structurally diverse lipidoids. From this library, we identified lipidoids that facilitate high levels of specific silencing of endogenous gene transcripts when formulated with either double-stranded small interfering RNA (siRNA) or single-stranded antisense 2'-O-methyl (2'-OMe) oligoribonucleotides targeting microRNA (miRNA). The safety and efficacy of lipidoids were evaluated in three animal models: mice, rats and nonhuman primates. The studies reported here suggest that these materials may have broad utility for both local and systemic delivery of RNA therapeutics.
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
- Alnylam Pharmaceuticals, Inc., 300 Third Street, Cambridge, Massachusetts 02142, USA.
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
- Department of Organic Chemistry, University of Geneva, 30 quai E. Ansermet 30, 1211 Geneva 4, Switzerland.
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
- Alnylam Europe AG, Fritz-Hornschuch-Str. 9, 95326 Kulmbach, Germany.
- Present addresses: Roche Kulmbach GmbH, Fritz-Hornschuch-Str. 9, 95326 Kulmbach, Germany (R.C., M.J. and H.-P.V.) and Regulus Therapeutics, 1896 Rutherford Road, Carlsbad, California 92008, USA (J.S.).
Correspondence to: Daniel G Anderson1 e-mail: dgander@mit.edu
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