RNAi 치료제 최근 연구 동향 - ksmcb.or.kr

1 RNAi .. ( ) ( ). ( 1).. dsRNA . RNA (RNA interference, RNAi) siRNA . 1998 Fire Mello .. 2006 10 RNAi . antisense, ribozymes . [1]. RNAi RNA (dsRNA) . RNA . , Dicer siRNA . 21-23bp RNA . RNA .. siRNA (short interfering RNA) . , siRNA . siRNA RISC (RNA induced silencing complex) .. Argonaute-2 , , .. RISC . microRNA(mRNA) . , , , , . 01 . MOLECULAR AND CELLULAR BIOLOGY NEWSLETTER. 1. siRNA . [2].. siRNA RNAi .. ( 2). , siRNA .. RNAi siRNA 50% 30 .. , RNAi .. siRNA .. siRNA , [3].. , RNAi , .. RNAi RNA RES (Reticuloendothelial system)/.. MPS (mononuclear phagocytic system) . [4-5]. , .. siRNA (40-50 negative phosphate charge) . , siRNA siRNA . , RNA . siRNA.

2 , . siRNA mRNA . off-target-effect . [6]. , siRNA .. siRNA .. 1. RNAi 2. siRNA . 2017 | 3 02.. 2. siRNA siRNA . poly amidoamine (PAMAM) poly (propylenimine) (PPI) . siRNA RNase .. , siRNA .. 2'-OH 2-O-methyl, 2-H, siRNA . 2-fluoro [7]. [11].. D-glucoseamines N-acetyl-D-glucosamines . [8]. 5' , acetyl-D-glucosamines pH. 3' overhang siRNA . mRNA off- . target effect [9-10] ( 3 a).. /siRNA CHOK1 . Naked siRNA HEK 293 [12].. /siRNA . siRNA in vivo .. , PEI [13]. , . (polyethylenimine), PLL (poly-l-lysine), , polyarginine PEG . ( 3 b, c).. , ( 3 d).. siRNA . [14].. RNase naked siRNA siRNA . siRNA .. PEI siRNA .. , siRNA .. , , . / . 3. siRNA . 03 . MOLECULAR AND CELLULAR BIOLOGY NEWSLETTER.

3 [18]. 1 . siRNA siRNA .. AMD, DME, NAION .. (RSV, HCV) siRNA . , , , . siRNA off-target .. Bevasiranib 3 . [15] ( 3 e). exosome siRNA , AGN-745 off-target effect , oligoncolotide , RNAi- 2 . TKM ApoB . microsponges siRNA 1 . siRNA . siRNA . [16-17]. TLR (Toll Like Receptor) .. naked siRNA I5NP. 2 . 3. RNAi .. siRNA . siRNA siRNA Nucleic acid lipid particle (SNALP) ALN- . 2004 siRNA RNAi VSP02 1 , . , 20 siRNA 50% -VEGF . SNALP . 1. siRNA . CTA Drug name Target disease Delivery route Vehicle Phase Status Company 2004 siRNA-027 AMD Intravitreal Free siRNA Terminated Allergan 2005 Bevasiranib AMD/DME Intravitreal Free siRNA Terminated OPKO Health, Inc. 2007 PF-04523655 AMD/DME Intravitreal Free siRNA Completed Quark/Pfizeer 2008 TD101 PC Intravitreal Free siRNA b Completed TransDerm/IPCC.

4 2009 SPC3649 HCV Subcutaneous LNA siRNA a Active Santaris 2009 QPI-1007 NAION Intravitreal Free siRNA Active Quark Pharma 2009 SYL040012 Intraocular pressure Eye drop Free siRNA Completed Sylentis 2011 SYL1001 Dry eye/ocular pain Eye drop Free siRNA Active Sylentis 2007 ALN-RSV01 RSV Nebulization Free siRNA b Completed Alnylam/Cubist 2008 15NP AKI Free siRNA Active Quark Phama 2008 ALN-VSP02 Solid tumor SNALP Completed Alnylam/Tekmira 2009 TKM-ApoB High cholesterol SNALP Terminated Tekmira 2009 ALN-TTR01 ATTR SNALP Completed Alnylam 2009 Atu027 Advanced solid tumor Lipoplex Completed Silence Therapeutics 2010 siG12D LODER Advanced pancreatic cancer LODER polymer Active Silenseed Ltd, 2011 ALN-PCS02 LDL-C SNALP Completed Alnylam 2008 CALAA-01 Solid tumor Polyplex Terminated Calando Pharma : clinical trial approval (CTA); age-related macular edema (AMD); diabetic macular edema (DME); Pachyonychia Congenital (PC); Hepatitis C Viral (HCV); transthyretin (TTR) mediated amyloidosis (ATTR); Acute Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION); respiratory syncytial virus (RSV); Acute Kidney Injury (AKI); low density lipoprotein-cholesterol (LDL-C).

5 : 2017 | 3 04.. ALN-TTR01 transthyretin (TTR) . , siRNA .. ATTR siRNA ALN-TTR02 , . TTR 94 . , , [19]. RNAi Atu027 . AtuPLEX 1 .. 33 27 siRNA . [20].. 21 RNAi SAMiRNA siRNA .. RNAi . off-target effect .. SAMiRNA.. RNAi . 1. Fire, A., Xu S., Montgomery, , Kostas, , Driver, , Mello, . (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 391, 806-11. siRNA . RNAi 2. Seton-Rogers S. (2012) Therapeutics: siRNAs jump the hurdle. Nature RNA RNAi Rev Cancer. 12, 376 7.. 3. Van de Water, , Boerman, , Wouterse, , Peters, , Russel, OLX101 , Masereeuw, R. (2006) intravenously administered short interfering RNA accumulates in the kidney and selectively suppresses gene OLX-201.

6 Function in renal proximal tubules. Drug Metab Dispos. 34,1393-7.. siRNA miRNA . 4. Owens, 3rd, Peppas, (2006) Opsonization, biodistribution, off-target effect miRNA . and pharmacokinetics of polymeric nanoparticles. Int. J. Pharm. 307, , 6 (Pivot) miRNA 93 102. siRNA-6pi . 5. Peer, D., Lieberman, J. (2011) Special delivery: targeted therapy with 2015 small RNAs, Gene Ther. 18, 1127 33.. 6. Zhou, Y., Zhang. C., Liang. W. (2014) Development of RNAi technology . for targeted therapy a track of siRNA based agents to RNAi therapeutics. J Control Release. 193, 270-81. 7. Deleavey, , Damha, (2012) Designing chemically modified 4. RNAi oligonucleotides for targeted gene silencing.

7 Chem Biol. 19, 937-54. 8. Choung, S., Kim, , Kim, S., Park, , Choi, (2006) Chemical siRNA modification of siRNAs to improve serum stability without loss of . efficacy, Biochem. Biophys ResCommun. 342, 919 27. siRNA . 9. Bramsen, , Laursen, , Nielsen, , Hansen, , Bus, C., off target effect . Langkjaer, N., Babu, , H jland, T., Abramov, M., Van Aerschot, A., Odadzic, D., Smicius, R., Haas, J., Andree, C., Barman, J., Wenska, M., , siRNA . Srivastava, P., Zhou, C., Honcharenko, D., Hess, S., M ller, E., Bobkov, . , Mikhailov, , Fava, E., Meyer, , Chattopadhyaya, J., Zerial, M., , RNAi Engels, , Herdewijn, P., Wengel, J., Kjems, J. (2009) A large-scale 05 . MOLECULAR AND CELLULAR BIOLOGY NEWSLETTER.

8 Chemical modification screen identifies design rules to generate 18. Burnett, , Rossi, , Tiemann, K. (2011) Current progress of siRNA/. siRNAs with high activity, high stability and low toxicity, Nucleic Acids shRNA therapeutics in clinical trials. Biotechnol J. 6, 1130 46. Res. 37, 2867 81. 19. Coelho, T., Adams, D., Silva, A., Lozeron, P., Hawkins, , Mant, T., 10. Amarzguioui, M., Rossi, (2008) Principles of Dicer substrate Perez, J., Chiesa, J., Warrington, S., Tranter, E., Munisamy, M., Falzone, (D-siRNA) design and function, Methods Mol Biol. 442, 3 10. R., Harrop, J., Cehelsky, J., Bettencourt, , Geissler, M., Butler, , Sehgal, A., Meyers, , Chen Q, Borland, T.

9 , Hutabarat, , Clausen, 11. Liu, X., Wu, J., Yammine, M., Zhou, J., Posocco, P., Vie,l S., Liu, C., , Alvarez, R., Fitzgerald, K., Gamba-Vitalo, C., Nochur, , Vaishnaw, Ziarelli, F., Fermeglia, M., Pric,l S,, Victorero, G., Nguyen, C., Erbacher, , Sah, , Gollob, , Suhr, (2013) Safety and efficacy of RNAi P., Behr, , Peng, L. (2011) Structurally flexible triethanolamine core therapy for transthyretin amyloidosis, N Engl J Med. 369, 819 29. PAMAM dendrimers are effective nanovectors for DNA transfection in vitro and in vivo to the mouse thymus. Bioconjug Chem. 22, 2461 73. 20. Zhou, Y., Zhang, C., Liang, W. (2014) Development of RNAi technology for targeted therapy--a track of siRNA based agents to RNAi 12.

10 Katas, H., Alpar, (2006) Development and characterisation of therapeutics. J Control Release. 193,270-81. chitosan nanoparticles for siRNA delivery, J Control Release. 115, 216 225. 13. Mao, S., Sun, W., Kissel, T. (2010) Chitosan-based formulations for delivery of DNA and siRNA, Adv. Drug Deliv Rev. 62, 12 27. 14. Ravi a, M., Cubillo, E., Olmeda, D., Novoa-Carballal, R., Fernandez- Megia, E., Riguera, R., S nchez, A., Cano, A., Alonso, (2010) . Hyaluronic acid/chitosan-g-poly(ethyleneglycol) nanoparticles for gene therapy: an application for pDNA and siRNA delivery. Pharm Res. 27, 2544 55.. 2003-2007 . 15. Jeong, , Mok, H., Oh, , Park, (2009) siRNA conjugate delivery 2007-2009 University of Utah.