Nonviral delivery of synthetic siRNAs in vivo
Saghir Akhtar, Ibrahim F. Benter
Saghir Akhtar, Ibrahim F. Benter
Published December 3, 2007
Citation Information: J Clin Invest. 2007;117(12):3623-3632. https://doi.org/10.1172/JCI33494.
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Nonviral delivery of synthetic siRNAs in vivo

Abstract

Sequence-specific gene silencing using small interfering RNA (siRNA) is a Nobel prize–winning technology that is now being evaluated in clinical trials as a potentially novel therapeutic strategy. This article provides an overview of the major pharmaceutical challenges facing siRNA therapeutics, focusing on the delivery strategies for synthetic siRNA duplexes in vivo, as this remains one of the most important issues to be resolved. This article also highlights the importance of understanding the genocompatibility/toxicogenomics of siRNA delivery reagents in terms of their impact on gene-silencing activity and specificity. Collectively, this information is essential for the selection of optimally acting siRNA delivery system combinations for the many proposed applications of RNA interference.

Authors

Saghir Akhtar , Ibrahim F. Benter

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Figure 1

The pharmaceutical challenges to effective siRNA delivery and activity in vivo.

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The pharmaceutical challenges to effective siRNA delivery and activity i...
The challenges for effective siRNA delivery and activity in vivo range from the effective empirical or in silico design and selection of an effective siRNA sequence to its chemical modification or formulation with delivery vectors to improve biological stability and pharmacokinetics (steps i–iv). Optimally designed and formulated siRNA should then efficiently enter target cells and escape endosomal and other intracellular compartments to become highly bioavailable inside the cells so as to exert sequence-specific gene-silencing activity with no or minimal effects on nontargeted genes or inadvertent stimulation of the immune system (steps v–x) (see text for detailed explanation).