Therapeutic application of RNAi: is mRNA targeting finally ready for prime time?
Dirk Grimm, Mark A. Kay
Dirk Grimm, Mark A. Kay
Published December 3, 2007
Citation Information: J Clin Invest. 2007;117(12):3633-3641. https://doi.org/10.1172/JCI34129.
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Therapeutic application of RNAi: is mRNA targeting finally ready for prime time?

Abstract

With unprecedented speed, RNA interference (RNAi) has advanced from its basic discovery in lower organisms to becoming a powerful genetic tool and perhaps our single most promising biotherapeutic for a wide array of diseases. Numerous studies document RNAi efficacy in laboratory animals, and the first clinical trials are underway and thus far suggest that RNAi is safe to use in humans. Yet substantial hurdles have also surfaced and must be surmounted before therapeutic RNAi applications can become a standard therapy. Here we review the most critical roadblocks and concerns for clinical RNAi transition, delivery, and safety. We highlight emerging solutions and concurrently discuss novel therapeutic RNAi-based concepts. The current rapid advances create realistic optimism that the establishment of RNAi as a new and potent clinical modality in humans is near.

Authors

Dirk Grimm, Mark A. Kay

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Figure 1

Mechanism of RNAi.

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Mechanism of RNAi. dsRNA is cleaved at specific sites by Dicer to form s...
dsRNA is cleaved at specific sites by Dicer to form siRNA. siRNA can also be produced either in vitro, after which it can be conjugated to other molecules for efficient delivery into the target cells, or within cells, via DNA-based vectors encoding shRNA. siRNA binds to RISC, the action of which exposes the antisense strand of siRNA and allows it to recognize mRNA with a complementary sequence. Upon mRNA binding to RISC, the mRNA is cleaved and degraded, resulting in the posttranslational silencing of gene expression. Figure modified from ref. 93.