Since the discovery of RNA interference (RNAi), excitement has grown over its potential therapeutic uses. Targeting RNAi pathways provides a powerful tool to change biological processes post-transcriptionally in various health conditions such as cancer or autoimmune diseases. Optimum design of shRNA, siRNA, and miRNA enhances stability and specificity of RNAi-based approaches whereas it has to reduce or prevent undesirable immune responses or off-target effects. Recent advances in understanding pathogenesis of autoimmune diseases have allowed application of these tools in vitro as well as in vivo with some degree of success. Further research on the design and delivery of effectors of RNAi pathway and underlying molecular basis of RNAi would warrant practical use of RNAi-based therapeutics in human applications. This review will focus on the approaches used for current therapeutics and their applications in autoimmune diseases, including rheumatoid arthritis and Sj？gren’s syndrome.
References
[1]
Filipowicz, W.; Bhattacharyya, S.N.; Sonenberg, N. Mechanisms of post-transcriptional regulation by microRNAs: Are the answers in sight? Nat. Rev. Genet. 2008, 9, 102–114.
[2]
Meister, G.; Tuschl, T. Mechanisms of gene silencing by double-stranded RNA. Nature 2004, 431, 343–349, doi:10.1038/nature02873.
[3]
Vlassov, A.V.; Korba, B.; Farrar, K.; Mukerjee, S.; Seyhan, A.A.; Ilves, H.; Kaspar, R.L.; Leake, D.; Kazakov, S.A.; Johnston, B.H. ShRNAs targeting hepatitis C: Effects of sequence and structural features, and comparision with siRNA. Oligonucleotides 2007, 17, 223–236, doi:10.1089/oli.2006.0069.
[4]
McAnuff, M.A.; Rettig, G.R.; Rice, K.G. Potency of siRNA versus shRNA mediated knockdown in vivo. J. Pharm. Sci. 2007, 96, 2922–2930, doi:10.1002/jps.20968.
[5]
Hughes, J.A.; Rao, G.A. Targeted polymers for gene delivery. Expert Opin. Drug Deliv. 2005, 2, 145–157, doi:10.1517/17425247.2.1.145.
[6]
Vorhies, J.S.; Nemunaitis, J.J. Nucleic Acid Aptamers for targeting of shRNA-based cancer therapeutics. Biologics 2007, 1, 367–376.
[7]
Kim, S.S.; Garg, H.; Joshi, A.; Manjunath, N. Strategies for Targeted Nonviral Delivery of siRNAs in vivo. Trends Mol. Med. 2009, 15, 491–500, doi:10.1016/j.molmed.2009.09.001.
[8]
Love, T.M.; Moffett, H.F.; Novina, C.D. Not miR-ly small RNAs: Big potential for microRNAs in therapy. J. Allergy Clin. Immunol. 2008, 121, 309–319, doi:10.1016/j.jaci.2007.12.1167.
[9]
Schwarz, D.S.; Ding, H.; Kennington, L.; Moore, J.T.; Schelter, J.; Burchard, J.; Linsley, P.S.; Aronin, N.; Xu, Z.; Zamore, P.D. Designing siRNA that distinguish between genes that differ by a single nucleotide. PLoS Genet. 2006, 2, e140, doi:10.1371/journal.pgen.0020140.
Layzer, J.M.; McCaffrey, A.P.; Tanner, A.K.; Huang, Z.; Kay, M.A.; Sullenger, B.A. In vivo activity of nuclease-resistant siRNAs. RNA 2004, 10, 766–771, doi:10.1261/rna.5239604.
[12]
Choung, S.; Kim, Y.J.; Kim, S.; Park, H.O.; Choi, Y.C. Chemical modification of siRNAs to improve serum stability without loss of efficacy. Biochem. Biophys. Res. Commun. 2006, 342, 919–927, doi:10.1016/j.bbrc.2006.02.049.
[13]
Wu, S.Y.; McMillan, N.A. Lipidic systems for in vivo siRNA delivery. AAPS J. 2009, 11, 639–652, doi:10.1208/s12248-009-9140-1.
[14]
Hart, S.L. Multifunctional nanocomplexes for gene transfer and gene therapy. Cell Biol Toxicol 2010, 26, 69–81, doi:10.1007/s10565-009-9141-y.
[15]
Mykhaylyk, O.; Zelphati, O.; Rosenecker, J.; Plank, C. SiRNA delivery by magnetofection. Curr. Opin. Mol. Ther. 2008, 10, 493–505.
[16]
Yu, B.; Zhao, X.; Lee, L.J.; Lee, R.J. Targeted delivery systems for oligonucleotide therapeutics. AAPS J. 2009, 11, 195–203, doi:10.1208/s12248-009-9096-1.
[17]
Endoh, T.; Ohtsuki, T. Cellular siRNA delivery using cell-penetrating peptides modified for endosomal escape. Adv. Drug Deliv. Rev. 2009, 61, 704–709, doi:10.1016/j.addr.2009.04.005.
Pauley, K.M.; Gauna, A.E.; Grichtchenko, I.I.; Chan, E.K.; Cha, S. A Secretagogue-small interfering RNA conjugate confers resistance to cytotoxicity in a cell model of Sjogren’s syndrome. Arthritis Rheum. 2011, 63, 3116–3125, doi:10.1002/art.30450.
[20]
Schiffelers, R.M.; Xu, J.; Storm, G.; Woodle, M.C.; Scaria, P.V. Effects of treatment with small interfering RNA on joint inflammation in mice with collagen-induced arthritis. Arthritis Rheum. 2005, 52, 1314–1318, doi:10.1002/art.20975.
[21]
Khoury, M.; Louis-Plence, P.; Escriou, V.; Noel, D.; Largeau, C.; Cantos, C.; Scherman, D.; Jorgensen, C.; Apparailly, F. Efficient new cationic liposome formulation for systemic delivery of small interfering RNA silencing tumor necrosis factor alpha in experimental arthritis. Arthritis Rheum. 2006, 54, 1867–1877, doi:10.1002/art.21876.
[22]
Komano, Y.; Yagi, N.; Onoue, I.; Kaneko, K.; Miyasaka, N.; Nanki, T. Arthritic joint-targeting small interfering RNA-encapsulated liposome: Implication for treatment strategy for rheumatoid arthritis. J. Pharmacol. Exp. Ther. 2012, 340, 109–113, doi:10.1124/jpet.111.185884.
[23]
Chen, S.Y.; Shiau, A.L.; Li, Y.T.; Lin, Y.S.; Lee, C.H.; Wu, C.L.; Wang, C.R. Suppression of collagen-induced arthritis by intra-articular lentiviral vector-mediated delivery of toll-like receptor 7 short hairpin RNA gene. Gene Ther. 2012, 19, 752–760, doi:10.1038/gt.2011.173.
Pauley, K.M.; Stewart, C.M.; Gauna, A.E.; Dupre, L.C.; Kuklani, R.; Chan, A.L.; Pauley, B.A.; Reeves, W.H.; Chan, E.K.; Cha, S. Altered miR-146a expression in Sjogren’s syndrome and its functional role in innate immunity. Eur. J. Immunol. 2011, 41, 2029–2039, doi:10.1002/eji.201040757.
[26]
Stanczyk, J.; Pedrioli, D.M.; Brentano, F.; Sanchez-Pernaute, O.; Kolling, C.; Gay, R.E.; Detmar, M.; Gay, S.; Kyburz, D. Altered expression of MICRORNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum. 2008, 58, 1001–1009, doi:10.1002/art.23386.
[27]
Li, J.; Wan, Y.; Guo, Q.; Zou, L.; Zhang, J.; Fang, Y.; Fu, X.; Liu, H.; Lu, L.; Wu, Y. Altered microRNA expression profile with miR-146a upregulation in CD4+ T cells from patients with rheumatoid arthritis. Arthritis Res. Ther. 2010, 12, R81, doi:10.1186/ar3006.
[28]
Nakasa, T.; Miyaki, S.; Okubo, A.; Hashimoto, M.; Nishida, K.; Ochi, M.; Asahara, H. Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum. 2008, 58, 1284–1292, doi:10.1002/art.23429.
[29]
Zilahi, E.; Tarr, T.; Papp, G.; Griger, Z.; Sipka, S.; Zeher, M. Increased microRNA-146a/b, TRAF6 Gene and decreased IRAK1 gene expressions in the peripheral mononuclear cells of patients with Sjogren’s syndrome. Immunol. Lett. 2012, 141, 165–168, doi:10.1016/j.imlet.2011.09.006.
[30]
Dai, Y.; Huang, Y.S.; Tang, M.; Lv, T.Y.; Hu, C.X.; Tan, Y.H.; Xu, Z.M.; Yin, Y.B. Microarray analysis of microRNA expression in peripheral blood cells of systemic lupus erythematosus patients. Lupus 2007, 16, 939–946, doi:10.1177/0961203307084158.
[31]
Tang, Y.; Luo, X.; Cui, H.; Ni, X.; Yuan, M.; Guo, Y.; Huang, X.; Zhou, H.; de Vries, N.; Tak, P.P.; et al. MicroRNA-146A Contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. Arthritis Rheum. 2009, 60, 1065–1075, doi:10.1002/art.24436.
[32]
Luo, X.; Yang, W.; Ye, D.Q.; Cui, H.; Zhang, Y.; Hirankarn, N.; Qian, X.; Tang, Y.; Lau, Y.L.; de Vries, N.; et al. A functional variant in microRNA-146a promoter modulates its expression and confers disease risk for systemic lupus erythematosus. PLoS Genet. 2011, 7, e1002128, doi:10.1371/journal.pgen.1002128.
[33]
Nakasa, T.; Shibuya, H.; Nagata, Y.; Niimoto, T.; Ochi, M. The inhibitory effect of microRNA-146a expression on bone destruction in collagen-induced arthritis. Arthritis Rheum. 2011, 63, 1582–1590, doi:10.1002/art.30321.
