Department of Chemical Engineering and Materials Science, Michigan State University, 428 S. Shaw Lane, Room 2527, East Lansing, MI 48824, USA;
Pharmaceuticals (Basel). 2013;6(4):440-68. doi: 10.3390/ph6040440.
While protein-based therapeutics is well-established in the market, development of nucleic acid therapeutics has lagged. Short interfering RNAs (siRNAs) represent an exciting new direction for the pharmaceutical industry. These small, chemically synthesized RNAs can knock down the expression of target genes through the use of a native eukaryotic pathway called RNA interference (RNAi). Though siRNAs are routinely used in research studies of eukaryotic biological processes, transitioning the technology to the clinic has proven challenging. Early efforts to design an siRNA therapeutic have demonstrated the difficulties in generating a highly-active siRNA with good specificity and a delivery vehicle that can protect the siRNA as it is transported to a specific tissue. In this review article, we discuss design considerations for siRNA therapeutics, identifying criteria for choosing therapeutic targets, producing highly-active siRNA sequences, and designing an optimized delivery vehicle. Taken together, these design considerations provide logical guidelines for generating novel siRNA therapeutics.
虽然基于蛋白质的治疗药物在市场上已经得到了很好的确立，但核酸治疗药物的开发却落后了。短干扰 RNA（siRNA）代表了制药行业一个令人兴奋的新方向。这些小的、化学合成的 RNA 可以通过利用称为 RNA 干扰（RNAi）的天然真核途径来敲低靶基因的表达。虽然 siRNA 通常用于真核生物过程的研究，但将该技术转化为临床应用已被证明具有挑战性。早期设计 siRNA 治疗药物的努力已经证明，生成具有高活性、良好特异性的 siRNA 以及能够保护 siRNA 在被递送到特定组织时的递送载体具有一定难度。在这篇综述文章中，我们讨论了 siRNA 治疗药物的设计考虑因素，确定了选择治疗靶点的标准、产生高活性 siRNA 序列以及设计优化的递送载体。综上所述，这些设计考虑因素为生成新型 siRNA 治疗药物提供了合理的指导原则。
