Artículos de revistas
Emerging Rna-based Drugs: Sirnas, Micrornas And Derivates
Registro en:
Central Nervous System Agents In Medicinal Chemistry. , v. 12, n. 3, p. 217 - 232, 2012.
10.2174/187152412802430138
2-s2.0-84866651259
Autor
Pereira T.C.
Lopes-Cendes I.
Institución
Resumen
An emerging new category of therapeutic agents based on ribonucleic acid has emerged and shown very promising in vitro, animal and pre-clinical results, known as small interfering RNAs (siRNAs), microRNAs mimics (miRNA mimics) and their derivates. siRNAs are small RNA molecules that promote potent and specific silencing of mutant, exogenous or aberrant genes through a mechanism known as RNA interference. These agents have called special attention to medicine since they have been used to experimentally treat a series of neurological conditions with distinct etiologies such as prion, viral, bacterial, fungal, genetic disorders and others. siRNAs have also been tested in other scenarios such as: control of anxiety, alcohol consumption, drug-receptor blockage and inhibition of pain signaling. Although in a much earlier stage, miRNAs mimics, anti-miRs and small activating RNAs (saRNAs) also promise novel therapeutic approaches to control gene expression. In this review we intend to introduce clinicians and medical researchers to the most recent advances in the world of siRNA- and miRNA-mediated gene control, its history, applications in cells, animals and humans, delivery methods (an yet unsolved hurdle), current status and possible applications in future clinical practice. © 2012 Bentham Science Publishers. 12 3 217 232 Napoli, C., Lemieux, C., Jorgensen, R., Introduction of a chimeric chalcone synthase gene into petunia results in reversible cosuppression of homologous genes in trans (1990) Plant Cell, 2 (4), pp. 279-289 Wightman, B., Ha, I., Ruvkun, G., Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans (1993) Cell, 75 (5), pp. 855-862 Meister, G., Tuschl, T., Mechanisms of gene silencing by doublestranded RNA (2004) Nature, 431, pp. 343-349 Elbashir, S.M., Harborth, J., Lendeckel, W., Yalcin, A., Weber, K., Tuschl, T., Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells (2001) Nature, 411, pp. 494-498 Holen, T., Amarzguioui, M., Wiiger, M.T., Babaie, E., Prydz, H., Positional effects of short interfering RNAs targeting the human coagulation trigger Tissue Factor (2002) Nucleic Acids Res., 30, pp. 1757-1766 Khvorova, A., Reynolds, A., Jayasena, S.D., Functional siRNAs and miRNAs exhibit strand bias (2003) Cell, 115, pp. 209-216 Reynolds, A., Leake, D., Boese, Q., Scaringe, S., Marshall, W.S., Khvorova, A., Rational siRNA design for RNA interference (2004) Nat. Biotechnol., 22, pp. 326-330 Layzer, J.M., McCaffrey, A.P., Tanner, A.K., Huang, Z., Kay, M.A., Sullenger, B.A., In vivo activity of nuclease-resistant siRNAs (2004) RNA, 10, pp. 766-771 Schiffelers, R.M., Ansari, A., Xu, J., Zhou, Q., Tang, Q., Storm, G., Molema, G., Woodle, M.C., Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle (2004) Nucleic Acids Res., 32, pp. e149 Soutschek, J., Akinc, A., Bramlage, B., Charisse, K., Constien, R., Donoghue, M., Elbashir, S., Vornlocher, H.P., Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs (2004) Nature, 432, pp. 173-178 Schröfelbauer, B., Hakata, Y., Landau, N.R., HIV-1 Vpr function is mediated by interaction with the damage-specific DNA-binding protein DDB1 (2007) Proc. Natl. Acad. Sci. U.S.A., 104, pp. 4130-4135 Folkman, J., Tumor angiogenesis: Therapeutic implications (1971) N. Engl. J. Med., 285, pp. 1182-1186 Sun, L., Hui, A.M., Su, Q., Vortmeyer, A., Kotliarov, Y., Pastorino, S., Passaniti, A., Fine, H.A., Neuronal and gliomaderived stem cell factor induces angiogenesis within the brain (2006) Cancer Cell, 9, pp. 287-300 Peters, K.G., Coogan, A., Berry, D., Marks, J., Iglehart, J.D., Kontos, C.D., Rao, P., Trogan, E., Expression of Tie2/Tek in breast tumour vasculature provides a new marker for evaluation of tumour angiogenesis (1998) Br. J. Cancer, 77, pp. 51-56 Gondi, C.S., Lakka, S.S., Dinh, D.H., Olivero, W.C., Gujrati, M., Rao, J.S., Intraperitoneal injection of a hairpin RNA-expressing plasmid targeting urokinase-type plasminogen activator (uPA) receptor and uPA retards angiogenesis and inhibits intracranial tumor growth in nude mice (2007) Clin. Cancer Res., 13, pp. 4051-4060 Pyrko, P., Schönthal, A.H., Hofman, F.M., Chen, T.C., Lee, A.S., The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas (2007) Cancer Res., 67, pp. 9809-9816 Goidts, V., Bageritz, J., Puccio, L., Nakata, S., Zapatka, M., Barbus, S., Toedt, G., Radlwimmer, B., RNAi screening in glioma stem-like cells identifies PFKFB4 as a key molecule important for cancer cell survival (2012) Oncogene, 31 (27), pp. 3235-3243 Wurdak, H., Zhu, S., Romero, A., Lorger, M., Watson, J., Chiang, C.Y., Zhang, J., Schultz, P.G., An RNAi screen identifies TRRAP as a regulator of brain tumor-initiating cell differentiation (2010) Cell Stem Cell, 6, pp. 37-47 Sheng, Z., Li, L., Zhu, L.J., Smith, T.W., Demers, A., Ross, A.H., Moser, R.P., Green, M.R., A genome-wide RNA interference screen reveals an essential CREB3L2-ATF5-MCL1 survival pathway in malignant glioma with therapeutic implications (2010) Nat Med., 16, pp. 671-677 Kim, Y.W., Liu, T.J., Koul, D., Tiao, N., Feroze, A.H., Wang, J., Powis, G., Yung, W.K., Identification of novel synergistic targets for rational drug combinations with PI3 kinase inhibitors using siRNA synthetic lethality screening against GBM (2011) Neuro Oncol., 13, pp. 367-375 Davis, M.E., Zuckerman, J.E., Choi, C.H., Seligson, D., Tolcher, A., Alabi, C.A., Yen, Y., Ribas, A., Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles (2010) Nature, 464, pp. 1067-1070 Fluiter, K., Mook, O.R., Baas, F., The therapeutic potential of LNA-modified siRNAs: Reduction of off-target effects by chemical modification of the siRNA sequence (2009) Methods Mol. Biol., 487, pp. 189-203 Musatov, S., Chen, W., Pfaff, D.W., Kaplitt, M.G., Ogawa, S., RNAi-mediated silencing of estrogen receptor {alpha} in the ventromedial nucleus of hypothalamus abolishes female sexual behaviors (2006) Proc. Natl. Acad. Sci. U.S.A., 103, pp. 10456-10460 Lasek, A.W., Janak, P.H., He, L., Whistler, J.L., Heberlein, U., Downregulation of mu opioid receptor by RNA interference in the ventral tegmental area reduces ethanol consumption in mice (2007) Genes Brain Behav., 6, pp. 728-735 Bahi, A., Boyer, F., Bussard, G., Dreyer, J.L., Silencing dopamine D3-receptors in the nucleus accumbens shell in vivo induces changes in cocaine-induced hyperlocomotion (2005) Eur. J. Neurosci., 21, pp. 3415-3426 Thakker, D.R., Natt, F., Hüsken, D., van der Putten, H., Maier, R., Hoyer, D., Cryan, J.F., siRNA-mediated knockdown of the serotonin transporter in the adult mouse brain (2005) Mol. Psychiatry, 10, pp. 782-789 Christoph, T., Grünweller, A., Mika, J., Schäfer, M.K., Wade, E.J., Weihe, E., Erdmann, V.A., Kurreck, J., Silencing of vanilloid receptor TRPV1 by RNAi reduces neuropathic and visceral pain in vivo (2006) Biochem. Biophys. Res. Commun., 350, pp. 238-243 Kasama, S., Kawakubo, M., Suzuki, T., Nishizawa, T., Ishida, A., Nakayama, J., RNA interference-mediated knock-down of transient receptor potential vanilloid 1 prevents forepaw inflammatory hyperalgesia in rat (2007) Eur. J. Neurosci., 25, pp. 2956-2963 Altier, C., Dale, C.S., Kisilevsky, A.E., Chapman, K., Castiglioni, A.J., Matthews, E.A., Evans, R.M., Zamponi, G.W., Differential role of N-type calcium channel splice isoforms in pain (2007) J. Neurosci, 27, pp. 6363-63673 Yang, C., Gagnon, D., Vachon, P., Tremblay, A., Levy, E., Massie, B., Michaud, J.L., Adenoviral-mediated modulation of Sim1 expression in the paraventricular nucleus affects food intake (2006) J. Neurosci., 26, pp. 7116-7120 Shishkina, G.T., Kalinina, T.S., Dygalo, N.N., Attenuation of μ2Aadrenergic receptor expression in neonatal rat brain by RNA interference or antisense oligonucleotide reduced anxiety in adulthood (2004) Neuroscience, 129, pp. 521-528 Hovatta, I., Tennant, R.S., Helton, R., Marr, R.A., Singer, O., Redwine, J.M., Ellison, J.A., Barlow, C., Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice (2005) Nature, 438, pp. 662-666 Morrissey, D.V., Lockridge, J.A., Shaw, L., Blanchard, K., Jensen, K., Breen, W., Hartsough, K., Polisky, B., Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs (2005) Nature Biotechnol., 23, pp. 1002-1007 Johnson, P.L., Truitt, W., Fitz, S.D., Minick, P.E., Dietrich, A., Sanghani, S., Träskman-Bendz, L., Shekhar, A., A key role for orexin in panic anxiety (2010) Nat. Med., 16, pp. 111-115 Kim, K.S., Lee, K.W., Baek, I.S., Lim, C.M., Krishnan, V., Lee, J.K., Nestler, E.J., Han, P.L., Adenylyl cyclase-5 activity in the nucleus accumbens regulates anxiety-related behavior (2008) J. Neurochem., 107, pp. 105-115 Bortolozzi, A., Castañé, A., Semakova, J., Santana, N., Alvarado, G., Cortés, R., Ferrés-Coy, A., Artigas, F., Selective siRNA-mediated suppression of 5-HT(1A) autoreceptors evokes strong anti-depressant-like effects (2012) Mol. Psychiatry, 17 (6), pp. 612-623 Bartel, D.P., MicroRNAs: Genomics, biogenesis, mechanism, and function (2004) Cell, 116, pp. 281-297 Sontheimer, E.J., Carthew, R.W., Silence from within: Endogenous siRNAs and miRNAs (2005) Cell, 122, pp. 9-12 Kiriakidou, M., Tan, G.S., Lamprinaki, S., De Planell-Saguer, M., Nelson, P.T., Mourelatos, Z., An mRNA m7G cap binding-like motif within human Ago2 represses translation (2007) Cell, 129, pp. 1141-1151 Mack, G.S., MicroRNA gets down to business (2007) Nat. Biotechnol., 25, pp. 631-638 Niu, Q.W., Lin, S.S., Reyes, J.L., Chen, K.C., Wu, H.W., Yeh, S.D., Chua, N.H., (2006) Nat. Biotechnol., 24, p. 1420 Calin, G.A., Dumitru, C.D., Shimizu, M., Bichi, R., Zupo, S., Noch, E., Aldler, H., Croce, C.M., Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia (2002) Proc. Natl. Acad. Sci. U.S.A., 99, pp. 15524-15529 Shi, B., Sepp-Lorenzino, L., Prisco, M., Linsley, P., deAngelis, T., Baserga, R., Micro RNA 145 targets the insulin receptor substrate-1 and inhibits the growth of colon cancer cells (2007) J. Biol. Chem., 282, pp. 32582-32590 Robbins, M., Judge, A., Liang, L., McClintock, K., Yaworski, E., McLachlan, I., 2'-O-Methyl-modified RNAs act as TLR7 antagonists (2007) Mol. Ther., 15, pp. 1663-1669 Musiyenko, A., Bitko, V., Barik, S., Ectopic expression of miR-126*, an intronic product of the vascular endothelial EGF-like 7 gene, regulates prostein translation and invasiveness of prostate cancer LNCaP cells (2008) J. Mol. Med., 86, pp. 313-322 Tsuda, N., Ishiyama, S., Li, Y., Ioannides, C.G., Abbruzzese, J.L., Chang, D.Z., Synthetic microRNA designed to target glioma associated antigen 1 transcription factor inhibits division and induces late apoptosis in pancreatic tumor cells (2006) Clin. Cancer Res., 12, pp. 6557-6564 Nan, Y., Han, L., Zhang, A., Wang, G., Jia, Z., Yang, Y., Yue, X., Kang, C., MiRNA-451 plays a role as tumor suppressor in human glioma cells (2010) Brain Res., 1359, pp. 14-21 Schratt, G.M., Tuebing, F., Nigh, E.A., Kane, C.G., Sabatini, M.E., Kiebler, M., Greenberg, M.E., A brain-specific microRNA regulates dendritic spine development (2006) Nature, 439, pp. 283-289 Stern-Ginossar, N., Elefant, N., Zimmermann, A., Wolf, D.G., Saleh, N., Biton, M., Horwitz, E., Mandelboim, O., Host immune system gene targeting by a viral miRNA (2007) Science, 317, pp. 376-381 Lecellier, C.H., Dunoyer, P., Arar, K., Lehmann-Che, J., Eyquem, S., Himber, C., Saïb, A., Voinnet, O., A cellular microRNA mediates antiviral defense in human cells (2005) Science, 308, pp. 557-560 Sullivan, C.S., Grundhoff, A.T., Tevethia, S., Pipas, J.M., Ganem, D., SV40-encoded microRNAs regulate viral gene expression and reduce susceptibility to cytotoxic T cells (2005) Nature, 435, pp. 682-686 Ebert, M.S., Neilson, J.R., Sharp, P.A., MicroRNA sponges: Competitive inhibitors of small RNAs in mammalian cells (2007) Nat. Methods, 4, pp. 721-726 Ebert, M.S., Sharp, P.A., MicroRNA sponges: Progress and possibilities (2010) RNA, 16, pp. 2043-2050 Kluiver, J., Gibcus, J.H., Hettinga, C., Adema, A., Richter, M.K., Halsema, N., Slezak-Prochazka, I., van den Berg, A., Rapid generation of microRNA sponges for microRNA inhibition (2012) PLoS One, 7, pp. e29275 Fisher, M., Abramov, M., Van Aerschot, A., Xu, D., Juliano, R.L., Herdewijn, P., Inhibition of MDR1 expression with altritolmodified siRNAs (2007) Nucleic Acids. Res., 35, pp. 1064-1074 Li, L.C., Okino, S.T., Zhao, H., Pookot, D., Place, R.F., Urakami, S., Enokida, H., Dahiya, R., Small dsRNAs induce transcriptional activation in human cells (2006) Proc. Natl. Acad. Sci. U.S.A., 103, pp. 17337-17342 Janowski, B.A., Younger, S.T., Hardy, D.B., Ram, R., Huffman, K.E., Corey, D.R., Activating gene expression in mammalian cells with promoter-targeted duplex RNAs (2007) Nat. Chem. Biol., 3, pp. 166-173 Check, E., RNA interference: Hitting the on switch (2007) Nature, 448, pp. 855-858 Huang, V., Qin, Y., Wang, J., Wang, X., Place, R.F., Lin, G., Lue, T.F., Li, L.C., RNAa is conserved in mammalian cells (2010) PLoS One, 5, pp. e8848 Place, R.F., Li, L.C., Pookot, D., Noonan, E.J., Dahiya, R., MicroRNA-373 induces expression of genes with complementary promoter sequences (2008) Proc. Natl. Acad. Sci. U.S.A., 105, pp. 1608-1613 Noma, K., Sugiyama, T., Cam, H., Verdel, A., Zofall, M., Jia, S., Moazed, D., Grewal, S.I., RITS acts in cis to promote RNA interference-mediated transcriptional and post-transcriptional silencing (2004) Nat. Genet., 36, pp. 1174-1180 Morris, K.V., Chan, S.W., Jacobsen, S.E., Looney, D.J., Small interfering RNA-induced transcriptional gene silencing in human cells (2004) Science, 305, pp. 1289-1292 Vastenhouw, N.L., Brunschwig, K., Okihara, K.L., Müller, F., Tijsterman, M., Plasterk, R.H., Gene expression: Long-term gene silencing by RNAi (2006) Nature, 24, pp. 442+882 Zhang, H.Y., Du, Q., Wahlestedt, C., Liang, Z., RNA Interference with chemically modified siRNA (2006) Curr. Top. Med. Chem., 6, pp. 893-900 Hoerter, J.A., Walter, N.G., Chemical modification resolves the asymmetry of siRNA strand degradation in human blood serum (2007) RNA, 13, pp. 1887-1893 Dowler, T., Bergeron, D., Tedeschi, A.L., Paquet, L., Ferrari, N., Damha, M.J., Improvements in siRNA properties mediated by 2'-deoxy-2'-fluoro-μ-d-arabinonucleic acid (FANA) (2006) Nucleic Acids Res., 34, pp. 1669-1675 Sipa, K., Sochacka, E., Kazmierczak-Baranska, J., Maszewska, M., Janicka, M., Nowak, G., Nawrot, B., Effect of base modifications on structure, thermodynamic stability, and gene silencing activity of short interfering RNA (2007) RNA, 13, pp. 1301-1316 Birmingham, A., Anderson, E.M., Reynolds, A., Ilsley-Tyree, D., Leake, D., Fedorov, Y., Baskerville, S., Khvorova, A., 3' UTR seed matches, but not overall identity, are associated with RNAi offtargets (2006) Nat. Methods, 3, pp. 199-204 Lewis, B.P., Burge, C.B., Bartel, D.P., Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets (2005) Cell, 120, pp. 15-20 Grimson, A., Farh, K.K., Johnston, W.K., Garrett-Engele, P., Lim, L.P., Bartel, D.P., MicroRNA targeting specificity in mammals: Determinants beyond seed pairing (2007) Mol. Cell, 27, pp. 91-105 Towne, C., Setola, V., Schneider, B.L., Aebischer, P., Neuroprotection by gene therapy targeting mutant SOD1 Watts, J.K., Choubdar, N., Sadalapure, K., Robert, F., Wahba, A.S., Pelletier, J., Pinto, B.M., Damha, M.J., 2'-Fluoro-4'-thioarabino-modified oligonucleotides: Conformational switches linked to siRNA activity (2007) Nucleic Acids Res., 35, pp. 1441-1451 Gaglione, M., Messere, A., Recent progress in chemically modified siRNAs (2010) Mini Rev. Med. Chem., 10 (7), pp. 578-595 Brummelkamp, T.R., Bernards, R., Agami, R., A system for stable expression of short interfering RNAs in mammalian cells (2002) Science, 296, pp. 550-553 Hohjoh, H., Enhancement of RNAi activity by improved siRNA duplexes (2004) FEBS Lett., 557, pp. 193-198 Kim, D.H., Behlke, M.A., Rose, S.D., Chang, M.S., Choi, S., Rossi, J.J., Synthetic dsRNA Dicer substrates enhance RNAi potency and efficacy (2005) Nat. Biotechnol., 23, pp. 222-226 Yang, D., Buchholz, F., Huang, Z., Goga, A., Chen, C.Y., Brodsky, F.M., Bishop, J.M., Short RNA duplexes produced by hydrolysis with Escherichia coli RNase III mediate effective RNA interference in mammalian cells (2002) Proc. Natl. Acad. Sci. U.S.A., 99, pp. 9942-9947 Sun, X., Rogoff, H.A., Li, C.J., Asymmetric RNA duplexes mediate RNA interference in mammalian cells (2008) Nat. Biotechnol., 26 (12), pp. 1379-1382 Chu, C.Y., Rana, T.M., Potent RNAi by short RNA triggers (2008) RNA, 14 (9), pp. 1714-1719 Bolcato-Bellemin, A.L., Bonnet, M.E., Creusat, G., Erbacher, P., Behr, J.P., Sticky overhangs enhance siRNA-mediated gene silencing (2007) Proc. Natl. Acad. Sci. U.S.A., 104 (41), pp. 16050-16055 Seyhan, A.A., Vlassov, A.V., Johnston, B.H., RNA interference from multimeric shRNAs generated by rolling circle transcription (2006) Oligonucleotides, 16 (4), pp. 353-363 Caplen, N.J., Taylor, J.P., Statham, V.S., Tanaka, F., Fire, A., Morgan, R.A., Rescue of polyglutamine-mediated cytotoxicity by double-stranded RNA-mediated RNA interference (2002) Hum. Mol. Genet., 11, pp. 175-184 Koldehoff, M., Steckel, N.K., Beelen, D.W., Elmaagacli, A.H., Therapeutic application of small interfering RNA directed against bcr-abl transcripts to a patient with imatinib-resistant chronic myeloid leukaemia (2007) Clin. Exp. Med., 7 (2), pp. 47-55 Koldehoff, M., Elmaagacli, A.H., Therapeutic targeting of gene expression by siRNAs directed against BCR-ABL transcripts in a patient with imatinib-resistant chronic myeloid leukemia (2009) Methods Mol. Biol., 487, pp. 451-466 Davis, M.E., The first targeted delivery of siRNA in humans via a self-assembling, cyclodextrin polymer-based nanoparticle: From concept to clinic (2009) Mol. Pharm., 6 (3), pp. 659-668 Leachman, S.A., Hickerson, R.P., Schwartz, M.E., Bullough, E.E., Hutcherson, S.L., Boucher, K.M., Hansen, C.D., Kaspar, R.L., First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder (2010) Mol. Ther., 18 (2), pp. 442-446 Davis, M.E., Zuckerman, J.E., Choi, C.H., Seligson, D., Tolcher, A., Alabi, C.A., Yen, Y., Ribas, A., Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles (2010) Nature, 464, pp. 1067-1070 Bahi, A., Boyer, F., Kolira, M., Dreyer, J.L., In vivo gene silencing of CD81 by lentiviral expression of small interference RNAs suppresses cocaine-induced behaviour (2005) J. Neurochem., 92, pp. 1243-1255 Pfeifer, A., Eigenbrod, S., Al-Khadra, S., Hofmann, A., Mitteregger, G., Moser, M., Bertsch, U., Kretzschmar, H., Lentivector-mediated RNAi efficiently suppresses prion protein and prolongs survival of scrapie-infected mice (2006) J. Clin. Invest., 116, pp. 3204-3210 Carmell, M.A., Zhang, L., Conklin, D.S., Hannon, G.J., Rosenquist, T.A., Germline transmission of RNAi in mice (2003) Nat. Struct. Biol., 10, pp. 91-92 Chen, Q., Butler, D., Querbes, W., Pandey, R.K., Ge, P., Maier, M.A., Zhang, L., Sah, D.W., Lipophilic siRNAs mediate efficient gene silencing in oligodendrocytes with direct CNS delivery (2010) J. Control Release, 144, pp. 227-232 Yang, T., Choi, M.K., Cui, F.D., Lee, S.J., Chung, S.J., Shim, C.K., Kim, D.D., Antitumor effect of paclitaxel-loaded PEGylated immunoliposomes against human breast cancer cells (2007) Pharm. Res., 24, pp. 2402-2411 Boado, R.J., Blood-brain barrier transport of non-viral gene and RNAi therapeutics (2007) Pharm. Res., 24, pp. 1772-1787 Zhang, Y., Zhang, Y.F., Bryant, J., Charles, A., Boado, R.J., Pardridge, W.M., Intravenous RNA interference gene therapy targeting the human epidermal growth factor receptor prolongs survival in intracranial brain cancer (2004) Clin. Cancer Res., 10, pp. 3667-3677 Kumar, P., Wu, H., McBride, J.L., Jung, K.E., Kim, M.H., Davidson, B.L., Lee, S.K., Manjunath, N., Transvascular delivery of small interfering RNA to the central nervous system (2007) Nature, 448, pp. 39-43 Alvarez-Erviti, L., Seow, Y., Yin, H., Betts, C., Lakhal, S., Wood, M.J., Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes (2011) Nat. Biotechnol., 29, pp. 341-345 Castilla, J., Saá, P., Soto, C., Detection of prions in blood (2005) Nat. Med., 11, pp. 982-985 Daude, N., Marella, M., Chabry, J., Specific inhibition of pathological prion protein accumulation by small interfering RNAs (2003) J. Cell Sci., 116, pp. 2775-2779 Atarashi, R., Moore, R.A., Sim, V.L., Hughson, A.G., Dorward, D.W., Onwubiko, H.A., Priola, S.A., Caughey, B., Ultrasensitive detection of scrapie prion protein using seeded conversion of recombinant prion protein (2007) Nat. Methods, 4, pp. 645-650 Pulford, B., Reim, N., Bell, A., Veatch, J., Forster, G., Bender, H., Meyerett, C., Zabel, M.D., Liposome-siRNA-peptide complexes cross the bloodbrain barrier and significantly decrease PrP on neuronal cells and PrP in infected cell cultures (2010) PLoS One, 5, pp. e11085 Leucht, C., Simoneau, S., Rey, C., Vana, K., Rieger, R., Lasmézas, C.I., Weiss, S., The 37 kDa/67 kDa laminin receptor is required for PrP(Sc) propagation in scrapie-infected neuronal cells (2003) EMBO Rep., 4, pp. 290-295 Pflanz, H., Vana, K., Mitteregger, G., Pace, C., Messow, D., Sedlaczek, C., Nikles, D., Weiss, S.F., Microinjection of lentiviral vectors expressing small interfering RNAs directed against laminin receptor precursor mRNA prolongs the pre-clinical phase in scrapie-infected mice (2009) J. Gen. Virol., 90, pp. 269-274 Ludewigs, H., Zuber, C., Vana, K., Nikles, D., Zerr, I., Weiss, S., Therapeutic approaches for prion disorders (2007) Expert Rev. Anti Infect. Ther., 5, pp. 613-630 Zafar, S., von Ahsen, N., Oellerich, M., Zerr, I., Schulz-Schaeffer, W.J., Armstrong, V.W., Asif, A.R., Proteomics approach to identify the interacting partners of cellular prion protein and characterization of Rab7a interaction in neuronal cells (2011) J. Proteome Res., 10, pp. 3123-3135 Jacque, J.M., Triques, K., Stevenson, M., Modulation of HIV-1 replication by RNA interference (2002) Nature, 418, pp. 435-438 Wiebusch, L., Truss, M., Hagemeier, C., Inhibition of human cytomegalovirus replication by small interfering RNAs (2004) J. Gen. Virol., 85, pp. 179-184 Palliser, D., Chowdhury, D., Wang, Q.Y., Lee, S.J., Bronson, R.T., Knipe, D.M., Lieberman, J., An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection (2006) Nature, 439, pp. 89-94 Gitlin, L., Karelsky, S., Andino, R., Short interfering RNA confers intracellular antiviral immunity in human cells (2002) Nature, 418, pp. 430-434 Novina, C.D., Murray, M.F., Dykxhoorn, D.M., Beresford, P.J., Riess, J., Lee, S.K., Collman, R.G., Sharp, P.A., siRNA-directed inhibition of HIV-1 infection (2002) Nat. Med., 8, pp. 681-686 Arteaga, H.J., Hinkula, J., van Dijk-Härd, I., Dilber, M.S., Wahren, B., Christensson, B., Mohamed, A.J., Smith, C.I., Choosing CCR5 or Rev siRNA in HIV-1 (2003) Nat. Biotechnol., 21, pp. 230-231 Ryo, A., Tsurutani, N., Ohba, K., Kimura, R., Komano, J., Nishi, M., Soeda, H., Yamamoto, N., SOCS1 is an inducible host factor during HIV-1 infection and regulates the intracellular trafficking and stability of HIV-1 Gag (2008) Proc. Natl. Acad. Sci. U.S.A., 105, pp. 294-299 Bortolamiol, D., Pazhouhandeh, M., Marrocco, K., Genschik, P., Ziegler-Graff, V., The Polerovirus F box protein P0 targets ARGONAUTE1 to suppress RNA silencing (2007) Curr. Biol., 17, pp. 1615-1621 Cullen, B.R., Is RNA interference involved in intrinsic antiviral immunity in mammals? (2006) Nat. Immunol., 7, pp. 563-567 Bivalkar-Mehla, S., Vakharia, J., Mehla, R., Abreha, M., Kanwar, J.R., Tikoo, A., Chauhan, A., Viral RNA silencing suppressors (RSS): Novel strategy of viruses to ablate the host RNA interference (RNAi) defense system (2011) Virus Res., 155, pp. 1-9 Churikov, N.A., Chistiakova, L.G., Zavil'gel'ski, G.B., Manukhov, I.V., RNA interference in Escherichia coli cells: The expression of molecules that are complementary to the lon gene mRNA in parallel orientation (2000) Genetika, 36, pp. 23-27. , In Russian Yanagihara, K., Tashiro, M., Fukuda, Y., Ohno, H., Higashiyama, Y., Miyazaki, Y., Hirakata, Y., Kohno, S., Effects of short interfering RNA against methicillin-resistant Staphylococcus aureus coagulase in vitro and in vivo (2006) J. Antimicrob. Chemother., 57, pp. 122-126 Schubert-Unkmeir, A., Konrad, C., Slanina, H., Czapek, F., Hebling, S., Frosch, M., Neisseria meningitidis induces brain microvascular endothelial cell detachment from the matrix and cleavage of occludin: A role for MMP-8 (2010) PLoS Pathog., 6, pp. e1000874 Long, M., Huang, S.H., Wu, C.H., Shackleford, G.M., Jong, A., Lipid raft/caveolae signaling is required for Cryptococcus neoformans invasion into human brain microvascular endothelial cells (2012) J. Biomed. Sci., 19, p. 19 Huang, S.H., Long, M., Wu, C.H., Kwon-Chung, K.J., Chan, Y.C., Chi, F., Lee, S., Jong, A., Invasion of Cryptococcus neoformans into human brain microvascular endothelial cells is mediated through the lipid rafts-endocytic pathway via the dual specificity tyrosine phosphorylation-regulated kinase 3 (DYRK3) (2011) J. Biol. Chem., 286, pp. 34761-34769 Chen, Y., Chen, J., Wen, H., Gao, P., Wang, J., Zheng, Z., Gu, J., S100A10 downregulation inhibits the phagocytosis of Cryptococcus neoformans by murine brain microvascular endothelial cells (2011) Microb. Pathog., 51, pp. 96-100 Qin, Q.M., Luo, J., Lin, X., Pei, J., Li, L., Ficht, T.A., de Figueiredo, P., Functional analysis of host factors that mediate the intracellular lifestyle of Cryptococcus neoformans (2011) PLoS Pathog., 7, pp. e1002078 Karlas, A., Machuy, N., Shin, Y., Pleissner, K.P., Artarini, A., Heuer, D., Becker, D., Meyer, T.F., Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication (2010) Nature, 463, pp. 818-822 Cronin, S.J., Nehme, N.T., Limmer, S., Liegeois, S., Pospisilik, J.A., Schramek, D., Leibbrandt, A., Penninger, J.M., Genome-wide RNAi screen identifies genes involved in intestinal pathogenic bacterial infection (2009) Science, 325, pp. 340-343 Kumar, D., Nath, L., Kamal, M.A., Varshney, A., Jain, A., Singh, S., Rao, K.V., Genome-wide analysis of the host intracellular network that regulates survival of Mycobacterium tuberculosis (2010) Cell., 140, pp. 731-743 Abdulla, M.H., O'Brien, T., Mackey, Z.B., Sajid, M., Grab, D.J., McKerrow, J.H., RNA interference of Trypanosoma brucei cathepsin B and L affects disease progression in a mouse model (2008) PLoS Negl. Trop. Dis., 2, pp. e298 Pereira, T.C., Pascoal, V.D., Marchesini, R.B., Maia, I.G., Magalhães, L.A., Zanotti-Magalhães, E.M., Lopes-Cendes, I., Schistosoma mansoni: Evaluation of an RNAi-based treatment targeting HGPRTase gene (2008) Exp. Parasitol., 118, p. 619 Chandramohanadas, R., Davis, P.H., Beiting, D.P., Harbut, M.B., Darling, C., Velmourougane, G., Lee, M.Y., Greenbaum, D.C., Apicomplexan parasites co-opt host calpains to facilitate their escape from infected cells (2009) Science, 324, pp. 794-797 Kasinathan, R.S., Morgan, W.M., Greenberg, R.M., Genetic knockdown and pharmacological inhibition of parasite multidrug resistance transporters disrupts egg production in Schistosoma mansoni (2011) PLoS Negl. Trop. Dis., 5, pp. e1425 Kumar, S., Molina-Cruz, A., Gupta, L., Rodrigues, J., Barillas-Mury, C., A peroxidase/dual oxidase system modulates midgut epithelial immunity in Anopheles gambiae (2010) Science, 327, pp. 1644-1648 Grab, D.J., Garcia-Garcia, J.C., Nikolskaia, O.V., Kim, Y.V., Brown, A., Pardo, C.A., Zhang, Y., Dumler, J.S., Protease activated receptor signaling is required for African trypanosome traversal of human brain microvascular endothelial cells (2009) PLoS Negl. Trop. Dis., 3, pp. e479 Maxwell, M.M., Pasinelli, P., Kazantsev, A.G., Brown Jr., R.H., RNA interference-mediated silencing of mutant superoxide dismutase rescues cyclosporin A-induced death in cultured neuroblastoma cells (2004) Proc. Natl. Acad. Sci. U.S. A, 101, pp. 3178-3183 Raoul, C., Abbas-Terki, T., Bensadoun, J.C., Guillot, S., Haase, G., Szulc, J., Henderson, C.E., Aebischer, P., Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS (2005) Nat. Med., 11, pp. 423-428 Ralph, G.S., Radcliffe, P.A., Day, D.M., Carthy, J.M., Leroux, M.A., Lee, D.C., Wong, L.F., Azzouz, M., Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model (2005) Nat. Med., 11, pp. 429-433 Saito, Y., Yokota, T., Mitani, T., Ito, K., Anzai, M., Miyagishi, M., Taira, K., Mizusawa, H., Transgenic small interfering RNA halts amyotrophic lateral sclerosis in a mouse model (2005) J. Biol. Chem., 280, pp. 42826-42830 Xia, X., Zhou, H., Huang, Y., Xu, Z., Allele-specific RNAi selectively silences mutant SOD1 and achieves significant therapeutic benefit in vivo (2006) Neurobiol. Dis., 23, pp. 578-586 Locatelli, F., Corti, S., Papadimitriou, D., Fortunato, F., Del Bo, R., Donadoni, C., Nizzardo, M., Comi, G.P., Fas small interfering RNA reduces motoneuron death in amyotrophic lateral sclerosis mice (2007) Ann. Neurol., 62, pp. 81-92 Xie, J., Awad, K.S., Guo, Q., RNAi knockdown of Par-4 inhibits neurosynaptic degeneration in ALS-linked mice (2005) J. Neurochem., 92, pp. 59-71 Goehler, H., Lalowski, M., Stelzl, U., Waelter, S., Stroedicke, M., Worm, U., Droege, A., Wanker, E.E., A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease (2004) Mol. Cell., 15, pp. 853-865 Qiu, Z., Norflus, F., Singh, B., Swindell, M.K., Buzescu, R., Bejarano, M., Chopra, R., Hersch, S.M., Sp1 is up-regulated in cellular and transgenic models of Huntington disease, and its reduction is neuroprotective (2006) J. Biol. Chem., 281, pp. 16672-16680 Harper, S.Q., Staber, P.D., He, X., Eliason, S.L., Martins, I.H., Mao, Q., Yang, L., Davidson, B.L., RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model (2005) Proc. Natl. Acad. Sci. U.S.A., 102, p. 5820 Wang, Y.L., Liu, W., Wada, E., Murata, M., Wada, K., Kanazawa, I., Clinico-pathological rescue of a model mouse of Huntington's disease by siRNA (2005) Neurosci. Res., 53, pp. 241-249 Rodriguez-Lebron, E., Denovan-Wright, E.M., Nash, K., Lewin, A.S., Mandel, R.J., Intrastriatal rAAV-mediated delivery of antihuntingtin shRNAs induces partial reversal of disease progression in R6/1 Huntington's disease transgenic mice (2005) Mol. Ther., 12, pp. 618-633 Machida, Y., Okada, T., Kurosawa, M., Oyama, F., Ozawa, K., Nukina, N., rAAV-mediated shRNA ameliorated neuropathology in Huntington disease model mouse (2006) Biochem. Biophys. Res. Commun., 343, pp. 190-197 Huang, B., Schiefer, J., Sass, C., Landwehrmeyer, G.B., Kosinski, C.M., Kochanek, S., High-capacity adenoviral vector-mediated reduction of huntingtin aggregate load in vitro and in vivo (2007) Hum. Gene Ther., 18, pp. 303-311 DiFiglia, M., Sena-Esteves, M., Chase, K., Sapp, E., Pfister, E., Sass, M., Yoder, J., Aronin, N., Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits (2007) Proc. Natl. Acad. Sci. U.S.A., 104, pp. 17204-17209 Horvath, L., van Marion, I., Taï, K., Nielsen, T.T., Lundberg, C.J., Knockdown of GAD67 protein levels normalizes neuronal activity in a rat model of Parkinson's disease (2011) Gene Med., 13, pp. 188-197 de Yñigo-Mojado, L., Martín-Ruíz, I., Sutherland, J.D., Efficient allele-specific targeting of LRRK2 R1441 mutations mediated by RNAi (2011) PLoS One., 6, pp. e21352 Gerard, M., Deleersnijder, A., Daniëls, V., Schreurs, S., Munck, S., Reumers, V., Pottel, H., Baekelandt, V., Inhibition of FK506 binding proteins reduces alpha-synuclein aggregation and Parkinson's disease-like pathology (2010) J. Neurosci., 30, pp. 2454-2463 He, G., Luo, W., Li, P., Remmers, C., Netzer, W.J., Hendrick, J., Bettayeb, K., Greengard, P., Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease (2010) Nature, 467, pp. 95-98 López-Tobón, A., Castro-Álvarez, J.F., Piedrahita, D., Boudreau, R.L., Gallego-Gómez, J.C., Cardona-Gómez, G.P., Silencing of CDK5 as potential therapy for Alzheimer's disease (2011) Rev. Neurosci., 22, pp. 143-152 Hu, J., Gagnon, K.T., Liu, J., Watts, J.K., Syeda-Nawaz, J., Bennett, C.F., Swayze, E.E., Corey, D.R., Allele-selective inhibition of ataxin-3 (ATX3) expression by antisense oligomers and duplex RNAs (2011) Biol. Chem., 392, pp. 315-325 Alves, S., Nascimento-Ferreira, I., Dufour, N., Hassig, R., Auregan, G., Nóbrega, C., Brouillet, E., de Almeida, L.P., Silencing ataxin-3 mitigates degeneration in a rat model of Machado-Joseph disease: No role for wild-type ataxin-3? (2010) Hum. Mol. Genet., 19, pp. 2380-2394 Nakano, I., Masterman-Smith, M., Saigusa, K., Paucar, A.A., Horvath, S., Shoemaker, L., Watanabe, M., Kornblum, H.I., Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors, including brain tumor stem cells (2008) J. Neurosci. Res., 86, p. 48 Horvath, S., Zhang, B., Carlson, M., Lu, K.V., Zhu, S., Felciano, R.M., Laurance, M.F., Mischel, P.S., Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target (2006) Proc. Natl. Acad. Sci. U.S.A., 103, pp. 17402-17407 Patry, C., Bouchard, L., Labrecque, P., Gendron, D., Lemieux, B., Toutant, J., Lapointe, E., Chabot, B., Small interfering RNA-mediated reduction in heterogeneous nuclear ribonucleoparticule A1/A2 proteins induces apoptosis in human cancer cells but not in normal mortal cell lines (2003) Cancer Res., 63, pp. 7679-7688