Overcoming obstacles to develop effective and safe siRNA therapeutics

Abstract

Background: RNA interference (RNAi) is a promising new therapeutic modality. By acting at the mRNA level, RNAi circumvents the druggability issue associated with many disease-driven genes. The lack of safe and effective methods to deliver RNAi therapeutics remains the primary technical hurdle that prevents full utilization of the potential of RNAi therapy. Objective: To examine progress in the therapeutic RNAi field and highlight remaining hurdles for the development of RNAi therapeutics. Methods: This review focuses on the design principles of delivery technologies that demonstrated target inhibition in vivo after systemic administration. Conclusion: Although many promising delivery technologies have been described, all current delivery platforms have limitations. However, using an optimal combination of disease indication, disease target and the most potent RNA trigger, it may be possible to advance RNAi therapeutics in the near term using an imperfect delivery vehicle. The availability of high-throughput assays to monitor/compare various delivery systems for their performance in vivo will be essential for programs that focus on siRNA delivery.

Keywords::

• delivery
• RNA interference
• RNAi
• siRNA
• systemic delivery
• therapy

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