J Korean Soc Transplant.  2015 Sep;29(3):101-108. 10.4285/jkstn.2015.29.3.101.

Current Prospects of RNA Interference-based Therapy in Organ Transplantation

• Kim JY

• KMID: 2202582
• DOI: http://doi.org/10.4285/jkstn.2015.29.3.101

Abstract

RNA interference (RNAi) is a normal cellular process in which small RNAs control gene expression. siRNAs introduced into cells suppress gene expression through their recognition and cleavage of cognate mRNAs in a sequence specific manner. Due to its highly specific mode of action, RNAi has recently been tested for treatment or prevention of various diseases including organ transplantation as well as basic biomedical research. However, to achieve clinical success, there are some important issues that should be fully validated. First, siRNAs should be properly designed to avoid off-target effects. Second, siRNAs must be modified so as not to induce innate immune responses. Third, selective delivery of siRNA into desired organs or tissues is required. Despite such prerequisites, siRNAs are thought to be superior to traditional small molecule drug in terms of new drug development. In addition, in case of heart and islet transplantation which probably requires preservation of organs or cultivation of tissues for a while, siRNAs can be added to preserving solution or medium to control target gene expression during this period. In many research studies, mediators of innate immune response, inflammation, and cell death have been tested for alleviation of tissue injury and immune rejection after transplantation as potent targets of RNAi. We suggest that elucidation of exact mechanisms for tissue injury and immune rejection and subsequent selection and validation of target of RNAi in future studies might be helpful in enabling RNAi-based therapy in clinical organ transplantation to become a reality.

Keyword

RNA interference; Small interfering RNA; Organ transplantation

MeSH Terms

Cell Death
Gene Expression
Heart
Immunity, Innate
Inflammation
Islets of Langerhans Transplantation
Organ Transplantation*
RNA Interference
RNA*
RNA, Messenger
RNA, Small Interfering
Transplants*
RNA
RNA, Messenger
RNA, Small Interfering

Reference

References

1). Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double stranded RNA in Caenorhabditis elegans. Nature. 1998; 391:806–11.

2). Hannon GJ. RNA interference. Nature. 2002; 418:244–51.

3). Zamore PD, Haley B. Ribo-gnome: the big world of small RNAs. Science. 2005; 309:1519–24.

4). Meister G, Tuschl T. Mechanisms of gene silencing by dou-ble-stranded RNA. Nature. 2004; 431:343–9.

5). Kim YK, Kim VN. Processing of intronic microRNAs. EMBO J. 2007; 26:775–83.

6). Shi Y. Mammalian RNAi for the masses. Trends Genet. 2003; 19:9–12.

7). Zou GM, Yoder MC. Application of RNA interference to study stem cell function: current status and future perspectives. Biol Cell. 2005; 97:211–9.

8). Bernstein E, Caudy AA, Hammond SM, Hannon GJ. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature. 2001; 409:363–6.

9). Hammond SM, Bernstein E, Beach D, Hannon GJ. An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature. 2000; 404:293–6.

10). Stevenson M. Therapeutic potential of RNA interference. N Engl J Med. 2004; 351:1772–7.

11). Elbashir SM, Martinez J, Patkaniowska A, Lendeckel W, Tuschl T. Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogaster embryo lysate. EMBO J. 2001; 20:6877–88.

12). Yin JQ, Wan Y. RNA-mediated gene regulation system: now and the future (Review). Int J Mol Med. 2002; 10:355–65.

13). Tijsterman M, Plasterk RH. Dicers at RISC; the mechanism of RNAi. Cell. 2004; 117:1–3.

14). Siolas D, Lerner C, Burchard J, Ge W, Linsley PS, Paddison PJ, et al. Synthetic shRNAs as potent RNAi triggers. Nat Biotechnol. 2005; 23:227–31.

15). Choi I, Cho BR, Kim D, Miyagawa S, Kubo T, Kim JY, et al. Choice of the adequate detection time for the accurate evaluation of the efficiency of siRNA-induced gene silencing. J Biotechnol. 2005; 120:251–61.

16). Wang L, Mu FY. A web-based design center for vec-tor-based siRNA and siRNA cassette. Bioinformatics. 2004; 20:1818–20.

17). Naito Y, Yamada T, Ui-Tei K, Morishita S, Saigo K. siDirect: highly effective, target-specific siRNA design software for mammalian RNA interference. Nucleic Acids Res. 2004; 32:W124–9.

18). Yuan B, Latek R, Hossbach M, Tuschl T, Lewitter F. siRNA Selection Server: an automated siRNA oligonucleotide prediction server. Nucleic Acids Res. 2004; 32:W130–4.

19). Henschel A, Buchholz F, Habermann B. DEQOR: a web-based tool for the design and quality control of siRNAs. Nucleic Acids Res. 2004; 32:W113–20.

20). Li L, Lin X, Khvorova A, Fesik SW, Shen Y. Defining the optimal parameters for hairpin-based knockdown constructs. RNA. 2007; 13:1765–74.

21). Harborth J, Elbashir SM, Vandenburgh K, Manninga H, Scaringe SA, Weber K, et al. Sequence, chemical, and structural variation of small interfering RNAs and short hairpin RNAs and the effect on mammalian gene silencing. Antisense Nucleic Acid Drug Dev. 2003; 13:83–105.

22). Jackson AL, Burchard J, Schelter J, Chau BN, Cleary M, Lim L, et al. Widespread siRNA “off-target” transcript silencing mediated by seed region sequence complemen-tarity. RNA. 2006; 12:1179–87.

23). Judge AD, Sood V, Shaw JR, Fang D, McClintock K, MacLachlan I. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat Biotechnol. 2005; 23:457–62.

24). Pei Y, Tuschl T. On the art of identifying effective and specific siRNAs. Nat Methods. 2006; 3:670–6.

25). Jackson AL, Bartz SR, Schelter J, Kobayashi SV, Burchard J, Mao M, et al. Expression profiling reveals off-target gene regulation by RNAi. Nat Biotechnol. 2003; 21:635–7.

26). Lin X, Ruan X, Anderson MG, McDowell JA, Kroeger PE, Fesik SW, et al. siRNA-mediated off-target gene silencing triggered by a 7 nt complementation. Nucleic Acids Res. 2005; 33:4527–35.

27). Birmingham A, Anderson EM, Reynolds A, Ilsley-Tyree D, Leake D, Fedorov Y, et al. 3'UTR seed matches, but not overall identity, are associated with RNAi off-targets. Nat Methods. 2006; 3:199–204.

28). Naito Y, Yamada T, Matsumiya T, Ui-Tei K, Saigo K, Morishita S. dsCheck: highly sensitive off-target search software for double stranded RNA-mediated RNA interference. Nucleic Acids Res. 2005; 33:W589–91.

29). Manche L, Green SR, Schmedt C, Mathews MB. Interactions between double-stranded RNA regulators and the protein kinase DAI. Mol Cell Biol. 1992; 12:5238–48.

30). Sledz CA, Holko M, de Veer MJ, Silverman RH, Williams BR. Activation of the interferon system by short-interfering RNAs. Nat Cell Biol. 2003; 5:834–9.

31). Kim DH, Behlke MA, Rose SD, Chang MS, Choi S, Rossi JJ. Synthetic dsRNA Dicer substrates enhance RNAi potency and efficacy. Nat Biotechnol. 2005; 23:222–6.

32). Kleinman ME, Yamada K, Takeda A, Chandrasekaran V, Nozaki M, Baffi JZ, et al. Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature. 2008; 452:591–7.

33). Hornung V, Guenthner-Biller M, Bourquin C, Ablasser A, Schlee M, Uematsu S, et al. Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat Med. 2005; 11:263–70.

34). Sioud M. Induction of inflammatory cytokines and interferon responses by double-stranded and single-stranded siRNAs is sequence-dependent and requires endosomal localization. J Mol Biol. 2005; 348:1079–90.

35). Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol. 2004; 5:730–7.

36). Meurs E, Chong K, Galabru J, Thomas NS, Kerr IM, Williams BR, et al. Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell. 1990; 62:379–90.

37). Judge AD, Bola G, Lee AC, MacLachlan I. Design of non-inflammatory synthetic siRNA mediating potent gene silencing in vivo. Mol Ther. 2006; 13:494–505.

38). Morrissey DV, Lockridge JA, Shaw L, Blanchard K, Jensen K, Breen W, et al. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat Biotechnol. 2005; 23:1002–7.

39). Semple SC, Akinc A, Chen J, Sandhu AP, Mui BL, Cho CK, et al. Rational design of cationic lipids for siRNA delivery. Nat Biotechnol. 2010; 28:172–6.

40). Czauderna F, Fechtner M, Dames S, Aygü n H, Klippel A, Pronk GJ, et al. Structural variations and stabilizing modifications of synthetic siRNAs in mammalian cells. Nucleic Acids Res. 2003; 31:2705–16.

41). Karikó K, Bhuyan P, Capodici J, Weissman D. Small interfering RNAs mediate sequence-independent gene suppression and induce immune activation by signaling through toll-like receptor 3. J Immunol. 2004; 172:6545–9.

42). Kim DH, Rossi JJ. Strategies for silencing human disease using RNA interference. Nat Rev Genet. 2007; 8:173–84.

43). Davidson BL, McCray PB Jr. Current prospects for RNA interference-based therapies. Nat Rev Genet. 2011; 12:329–40.

44). Lares MR, Rossi JJ, Ouellet DL. RNAi and small interfering RNAs in human disease therapeutic applications. Trends Biotechnol. 2010; 28:570–9.

45). Shim MS, Kwon YJ. Efficient and targeted delivery of siRNA in vivo. FEBS J. 2010; 277:4814–27.

46). Weinstein S, Peer D. RNAi nanomedicines: challenges and opportunities within the immune system. Nanotechnology. 2010; 21:232001.

47). Whitehead KA, Langer R, Anderson DG. Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov. 2009; 8:129–38.

48). Soutschek J, Akinc A, Bramlage B, Charisse K, Constien R, Donoghue M, et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature. 2004; 432:173–8.

49). Wolfrum C, Shi S, Jayaprakash KN, Jayaraman M, Wang G, Pandey RK, et al. Mechanisms and optimization of in vivo delivery of lipophilic siRNAs. Nat Biotechnol. 2007; 25:1149–57.

50). Wu Y, Navarro F, Lal A, Basar E, Pandey RK, Manoharan M, et al. Durable protection from Herpes Simplex Virus-2 transmission following intravaginal application of siRNAs targeting both a viral and host gene. Cell Host Microbe. 2009; 5:84–94.

51). Chen Q, Butler D, Querbes W, Pandey RK, Ge P, Maier MA, et al. Lipophilic siRNAs mediate efficient gene silencing in oligodendrocytes with direct CNS delivery. J Control Release. 2010; 144:227–32.

52). Zimmermann TS, Lee AC, Akinc A, Bramlage B, Bumcrot D, Fedoruk MN, et al. RNAi-mediated gene silencing in nonhuman primates. Nature. 2006; 441:111–4.

53). Geisbert TW, Lee AC, Robbins M, Geisbert JB, Honko AN, Sood V, et al. Postexposure protection of nonhuman primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study. Lancet. 2010; 375:1896–905.

54). Davis ME, Zuckerman JE, Choi CH, Seligson D, Tolcher A, Alabi CA, et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature. 2010; 464:1067–70.

55). Dassie JP, Liu XY, Thomas GS, Whitaker RM, Thiel KW, Stockdale KR, et al. Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-ex-pressing tumors. Nat Biotechnol. 2009; 27:839–49.

56). Zhou J, Swiderski P, Li H, Zhang J, Neff CP, Akkina R, et al. Selection, characterization and application of new RNA HIV gp 120 aptamers for facile delivery of Dicer substrate siRNAs into HIV infected cells. Nucleic Acids Res. 2009; 37:3094–109.

57). Kumar P, Ban HS, Kim SS, Wu H, Pearson T, Greiner DL, et al. T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice. Cell. 2008; 134:577–86.

58). Peer D, Park EJ, Morishita Y, Carman CV, Shimaoka M. Systemic leukocyte-directed siRNA delivery revealing cyclin D1 as an anti-inflammatory target. Science. 2008; 319:627–30.

59). Kim SS, Peer D, Kumar P, Subramanya S, Wu H, Asthana D, et al. RNAi-mediated CCR5 silencing by LFA-1-targeted nanoparticles prevents HIV infection in BLT mice. Mol Ther. 2010; 18:370–6.

60). Kumar P, Wu H, McBride JL, Jung KE, Kim MH, Davidson BL, et al. Transvascular delivery of small interfering RNA to the central nervous system. Nature. 2007; 448:39–43.

61). Kortylewski M, Swiderski P, Herrmann A, Wang L, Kowolik C, Kujawski M, et al. In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses. Nat Biotechnol. 2009; 27:925–32.

62). Molitoris BA, Dagher PC, Sandoval RM, Campos SB, Ashush H, Fridman E, et al. siRNA targeted to p53 attenuates ischemic and cisplatin-induced acute kidney injury. J Am Soc Nephrol. 2009; 20:1754–64.

63). Gupta PK. RNRNA: The 2006 Nobel Prize for Physiology or Medicine. Curr Sci. 2006; 91:1443.

64). Vaishnaw AK, Gollob J, Gamba-Vitalo C, Hutabarat R, Sah D, Meyers R, et al. A status report on RNAi therapeutics. Silence. 2010; 1:14.

65). Zheng X, Lian D, Wong A, Bygrave M, Ichim TE, Khoshniat M, et al. Novel small interfering RNA-containing solution protecting donor organs in heart transplantation. Circulation. 2009; 120:1099–107.

66). Zhang X, Beduhn M, Zheng X, Lian D, Chen D, Li R, et al. Induction of alloimmune tolerance in heart transplantation through gene silencing of TLR adaptors. Am J Transplant. 2012; 12:2675–88.

67). Leuschner F, Dutta P, Gorbatov R, Novobrantseva TI, Donahoe JS, Courties G, et al. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat Biotechnol. 2011; 9:1005–10.

68). Li F, Mahato RI. iNOS gene silencing prevents inflammatory cytokine-induced beta-cell apoptosis. Mol Pharm. 2008; 5:407–17.

69). Callewaert H, Gysemans C, Cardozo AK, Elsner M, Tiedge M, Eizirik DL, et al. Cell loss during pseudoislet formation hampers profound improvements in islet lentiviral transduction efficacy for transplantation purposes. Cell Transplant. 2007; 16:527–37.

70). Li F, Mahato RI. RNA interference for improving the outcome of islet transplantation. Adv Drug Deliv Rev. 2011; 63:47–68.

71). Ripoll E, Pluvinet R, Torras J, Olivar R, Vidal A, Franquesa M, et al. In vivo therapeutic efficacy of intrarenal CD40 silencing in a model of humoral acute rejection. Gene Ther. 2011; 18:945–52.

72). Bao C, Lv Z, Zhang X, Zhu J, Ding F, Zhang Y, et al. Suppression of cardiac allograft vasculopathy in mice by inhibition of CC-motif chemokine receptor 5. Transpl Immunol. 2012; 26:128–32.

73). Jia Y, Zhao Z, Xu M, Zhao T, Qiu Y, Ooi Y, et al. Prevention of renal ischemia-reperfusion injury by short hairpin RNA of endothelin A receptor in a rat model. Exp Biol Med (Maywood). 2012; 237:894–902.

74). Yang C, Jia Y, Zhao T, Xue Y, Zhao Z, Zhang J, et al. Naked caspase 3 small interfering RNA is effective in cold preservation but not in autotransplantation of porcine kidneys. J Surg Res. 2012; 181:342–54.

75). Shou Z, Xiao H, Xu Y, Wang Y, Yang Y, Jiang H, et al. SHARP-2 gene silencing by lentiviral-based short hairpin RNA interference prolonged rat kidney transplant recipients' survival time. J Int Med Res. 2009; 37:766–78.

76). Feng B, Chen G, Zheng X, Sun H, Zhang X, Zhang ZX, et al. Small interfering RNA targeting RelB protects against renal ischemia-reperfusion injury. Transplantation. 2009; 87:1283–9.

77). Zheng X, Zhang X, Feng B, Sun H, Suzuki M, Ichim T, et al. Gene silencing of complement C5a receptor using siRNA for preventing ischemia/reperfusion injury. Am J Pathol. 2008; 173:973–80.

78). Wang P, Yigit MV, Ran C, Ross A, Wei L, Dai G, et al. A theranostic small interfering RNA nanoprobe protects pancreatic islet grafts from adoptively transferred immune rejection. Diabetes. 2012; 61:3247–54.

79). Wang P, Yigit MV, Medarova Z, Wei L, Dai G, Schuetz C, et al. Combined small interfering RNA therapy and in vivo magnetic resonance imaging in islet transplantation. Diabetes. 2011; 60:565–71.

80). Cheng G, Zhu L, Mahato RI. Caspase-3 gene silencing for inhibiting apoptosis in insulinoma cells and human islets. Mol Pharm. 2008; 5:1093–102.