siRNA therapeutics: big potential from small RNAs

Abstract

RNA interference (RNAi) is now an umbrella term referring to post-transcriptional gene silencing mediated by either degradation or translation arrest of target RNA. This process is initiated by double-stranded RNA with sequence homology driving specificity. The discovery that 21-23 nucleotide RNA duplexes (small-interfering RNAs, siRNAs) mediate RNAi in mammalian cells opened the door to the therapeutic use of siRNAs. While much work remains to optimize delivery and maintain specificity, the therapeutic advantages of siRNAs for treatment of viral infection, dominant disorders, cancer, and neurological disorders show great promise. Gene Therapy (2005) 12, 5-11.

Combinational antitumor effect of siRNA against midkine and paclitaxel on growth of human prostate cancer xenografts

“…Furthermore, there is an intense research effort aimed at developing siRNAs as therapeutics against various diseases such as viral infections, neurodegenerative disorders, and cancers. 3 Midkine (MK), a heparin-binding growth factor, is a 13-kD protein rich in basic amino acids and cysteine. 4,5 MK is comparatively ubiquitous in many kinds of tumors, 6,7 such as esophageal, gastric, colon, pancreatic, hepatocellular, lung, breast, and urinary bladder carcinomas, neuroblastomas, and Wilms' tumors, while in normal adult tissue, its expression is usually low or undetectable.…”

“…After 3 weeks, when the tumors had reached an average volume of $50-80 mm 3 , the tumor-bearing nude mice were treated with MK siRNA together with atelocollagen. The final concentration of atelocollagen was 1.75% and that of the siRNA was 500 pmol/tumor (50 lL injection into each tumor from 10 lM solution).…”

Reconstituted influenza virus envelopes as an efficient carrier system for cellular delivery of small-interfering RNAs

“…The rapidly growing list of diseases for which siRNA-mediated therapy is under development includes infectious diseases, neurological disorders, acute liver failure, cancer, sepsis, inflammation and others (for reviews see Lieberman et al, 11 Ryther et al, 15 Wall and Shi, 16 Sioud 17 and Stevenson 46 ). Three basic approaches have been followed for the application of RNA interference in situ: delivery of small siRNA molecules, delivery of plasmid vectors encoding small hairpin (sh) RNAs, which are processed to siRNA molecules within the target cell, and use of viral vectors that encode shRNA or both strands of siRNA.…”

“…9,10 Moreover, RNA interference is being developed as a therapeutic strategy for diseases that are associated with overexpression of (mutant forms of) proteins like infectious diseases, cancer, neurological disorders and sepsis. [11][12][13][14][15] A major obstacle for the use of siRNAs in vivo has been the absence of efficient delivery systems suitable for transporting the molecules to the cytosol of appropriate target cells (for reviews see Lieberman et al, 11 Wall and Shi, 16 Sioud 17 and Downward 18 ). Cellular uptake of free siRNA is rather inefficient.…”

A small interfering RNA targeting proteinase‐activated receptor‐2 is effective in suppression of tumor growth in a Panc1 xenograft model

“…21 Furthermore, there is an intense research effort aimed at developing siRNAs as therapies against various diseases, including viral infections, neurodegenerative disorders and cancers. 22 Several researchers have investigated siRNAs in animal models. 23,24 In several studies, atelocollagen was used as a carrier of siRNAs.…”