171
Views
0
CrossRef citations to date
0
Altmetric
Review

Gene expression inhibitors for the treatment of liver fibrosis: drugs under preclinical and early clinical investigation

&
Pages 1133-1141 | Received 12 Sep 2023, Accepted 22 Nov 2023, Published online: 28 Nov 2023

References

  • Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134(6):1655–1669. doi: 10.1053/j.gastro.2008.03.003
  • Schuppan D. Liver fibrosis: common mechanisms and antifibrotic therapies. Clin Res Hepatol Gastroenterol. 2015;39(Suppl 1):S51–59. doi: 10.1016/j.clinre.2015.05.005
  • Trautwein C, Friedman SL, Schuppan D, et al. Hepatic fibrosis: concept to treatment. J Hepatol. 2015;62(1):S15–24. doi: 10.1016/j.jhep.2015.02.039
  • Lin Y, Mehta S, Küçük-McGinty H, et al. Drug target ontology to classify and integrate drug discovery data. J Biomed Semantics. 2017;8(1):50. doi: 10.1186/s13326-017-0161-x
  • Cheng Y, He C, Wang M, et al. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduct Target Ther. 2019;4(1):62. doi: 10.1038/s41392-019-0095-0
  • Gelato KA, Adler D, Ocker M, et al. Targeting epigenetic regulators for cancer therapy: modulation of bromodomain proteins, methyltransferases, demethylases, and microRnas. Expert Opin Ther Targets. 2016;20(7):783–799. doi: 10.1517/14728222.2016.1134490
  • Roux PP, Topisirovic I. Signaling pathways involved in the regulation of mRNA translation. Mol Cell Biol. 2018;38(12):e00070–18. doi: 10.1128/MCB.00070-18
  • Ramazi S, Zahiri J. Posttranslational modifications in proteins: resources, tools and prediction methods. Database (Oxford). 2021;2021:baab012. doi: 10.1093/database/baab012
  • Yang Y-H, Wen R, Yang N, et al. Roles of protein post-translational modifications in glucose and lipid metabolism: mechanisms and perspectives. Mol Med. 2023;29(1):93. doi: 10.1186/s10020-023-00684-9
  • Laham-Karam N, Pinto GP, Poso A, et al. Transcription and translation inhibitors in cancer treatment. Front Chem. 2020;8:276. doi: 10.3389/fchem.2020.00276
  • Food and Drug Administration, HHS. International Conference on Harmonisation. Guidance on S9 Nonclincal Evaluation for Anticancer Pharmaceuticals; availability. Notice. Fed Regist. 2010Mar 8;75( 44):10487–10488. PMID: 20383918.
  • Wu C, Cheng D, Peng Y, et al. Hepatic BRD4 is upregulated in liver fibrosis of various etiologies and positively correlated to fibrotic severity. Front Med. 2021;8:683506. doi: 10.3389/fmed.2021.683506
  • Ding N, Hah N, Yu RT, et al. BRD4 is a novel therapeutic target for liver fibrosis. Proc Natl Acad Sci U S A. 2015;112(51):15713–15718. doi: 10.1073/pnas.1522163112
  • Fu R, Zu S-J, Liu Y-J, et al. Selective bromodomain and extra-terminal bromodomain inhibitor inactivates macrophages and hepatic stellate cells to inhibit liver inflammation and fibrosis. Bioengineered. 2022;13(4):10914–10930. doi: 10.1080/21655979.2022.2066756
  • Middleton SA, Rajpal N, Cutler L, et al. BET inhibition Improves NASH and liver fibrosis. Sci Rep. 2018;8(1):17257. doi: 10.1038/s41598-018-35653-4
  • Kang J-H, Splinter PL, Trussoni CE, et al. The epigenetic Reader, bromodomain containing 2, mediates cholangiocyte senescence via interaction with ETS proto-oncogene 1. Gastroenterology. 2023;165(1):228–243.e2. doi: 10.1053/j.gastro.2023.03.235
  • Ettl T, Schulz D, Bauer R. The renaissance of cyclin dependent kinase inhibitors. Cancers. 2022;14(2):293. doi: 10.3390/cancers14020293
  • Shiekhattar R, Mermelstein F, Fisher RP, et al. Cdk-activating kinase complex is a component of human transcription factor TFIIH. Nature. 1995;374(6519):283–287. doi: 10.1038/374283a0
  • Nemet J, Jelicic B, Rubelj I, et al. The two faces of Cdk8, a positive/negative regulator of transcription. Biochimie. 2014;97:22–27. doi: 10.1016/j.biochi.2013.10.004
  • Tsai K-L, Sato S, Tomomori-Sato C, et al. A conserved mediator–CDK8 kinase module association regulates mediator–RNA polymerase II interaction. Nat Struct Mol Biol. 2013;20(5):611–619. doi: 10.1038/nsmb.2549
  • Peng J, Zhu Y, Milton JT, et al. Identification of multiple cyclin subunits of human P-TEFb. Genes Dev. 1998;12(5):755–762. doi: 10.1101/gad.12.5.755
  • Kwiatkowski N, Zhang T, Rahl PB, et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature. 2014;511(7511):616–620. doi: 10.1038/nature13393
  • Marineau JJ, Hamman KB, Hu S, et al. Discovery of SY-5609: a selective, noncovalent inhibitor of CDK7. J Med Chem. 2022;65(2):1458–1480. doi: 10.1021/acs.jmedchem.1c01171
  • Garralda E, Schram AM, Bedard PL, et al. A Phase I dose-escalation study of LY3405105, a covalent inhibitor of cyclin-dependent kinase 7, administered to patients with advanced solid tumors. Oncology. 2023;oyad215. doi: 10.1093/oncolo/oyad215
  • Hatcher JM, Vatsan PS, Wang E, et al. Development of highly potent and selective pyrazolopyridine inhibitor of CDK8/19. ACS Med Chem Lett. 2021;12(11):1689–1693. doi: 10.1021/acsmedchemlett.1c00300
  • Chen C, Huang C, Xu M, et al. Abstract 5982: A potent and selective CDK8 inhibitor ABM-3249 with excellent efficacies in multiple in vivo cancer models. Cancer Res. 2023;83(7_Supplement):5982. doi: 10.1158/1538-7445.AM2023-5982
  • Hofmann MH, Mani R, Engelhardt H, et al. Selective and potent CDK8/19 inhibitors enhance NK-Cell activity and promote tumor surveillance. Mol Cancer Ther. 2020;19(4):1018–1030. doi: 10.1158/1535-7163.MCT-19-0789
  • He X-L, Hu Y-H, Chen J-M, et al. SNS-032 attenuates liver fibrosis by anti-active hepatic stellate cells via inhibition of cyclin dependent kinase 9. Front Pharmacol. 2022;13:1016552. doi: 10.3389/fphar.2022.1016552
  • Cui D, Xu D, Yue S, et al. Recent advances in the pharmacological applications and liver toxicity of triptolide. Chem Biol Interact. 2023;382:110651. doi: 10.1016/j.cbi.2023.110651
  • Titov DV, Gilman B, He Q-L, et al. XPB, a subunit of TFIIH, is a target of the natural product triptolide. Nat Chem Biol. 2011;7(3):182–188. doi: 10.1038/nchembio.522
  • Manzo SG, Zhou Z-L, Wang Y-Q, et al. Natural product triptolide mediates cancer cell death by triggering CDK7-dependent degradation of RNA polymerase II. Cancer Res. 2012;72(20):5363–5373. doi: 10.1158/0008-5472.CAN-12-1006
  • Vispé S, DeVries L, Créancier L, et al. Triptolide is an inhibitor of RNA polymerase I and II–dependent transcription leading predominantly to down-regulation of short-lived mRNA. Mol Cancer Ther. 2009;8(10):2780–2790. doi: 10.1158/1535-7163.MCT-09-0549
  • Chong L-W, Hsu Y-C, Chiu Y-T, et al. Antifibrotic effects of triptolide on hepatic stellate cells and dimethylnitrosamine-intoxicated rats. Phytother Res. 2011;25(7):990–999. doi: 10.1002/ptr.3381
  • Huang R, Guo F, Li Y, et al. Activation of AMPK by triptolide alleviates nonalcoholic fatty liver disease by improving hepatic lipid metabolism, inflammation and fibrosis. Phytomedicine. 2021;92:153739. doi: 10.1016/j.phymed.2021.153739
  • Yuan Z, Wang J, Zhang H, et al. Triptolide increases resistance to bile duct ligation-induced liver injury and fibrosis in mice by inhibiting RELB. Front Nutr. 2022;9:1032722. doi: 10.3389/fnut.2022.1032722
  • Laursen TL, Siggaard CB, Kazankov K, et al. Time-dependent improvement of liver inflammation, fibrosis and metabolic liver function after successful direct-acting antiviral therapy of chronic hepatitis C. J Viral Hepat. 2020;27(1):28–35. doi: 10.1111/jvh.13204
  • Jackson RJ, Hellen CUT, Pestova TV. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat Rev Mol Cell Biol. 2010;11(2):113–127. doi: 10.1038/nrm2838
  • Aitken CE, Lorsch JR. A mechanistic overview of translation initiation in eukaryotes. Nat Struct Mol Biol. 2012;19(6):568–576. doi: 10.1038/nsmb.2303
  • Boyce M, Bryant KF, Jousse C, et al. A selective inhibitor of eIf2α dephosphorylation protects cells from ER stress. Science. 2005;307(5711):935–939. doi: 10.1126/science.1101902
  • Li J, Li X, Liu D, et al. Phosphorylation of eIf2α signaling pathway attenuates obesity-induced non-alcoholic fatty liver disease in an ER stress and autophagy-dependent manner. Cell Death Dis. 2020;11(12):1069. doi: 10.1038/s41419-020-03264-5
  • Zarei M, Pujol E, Quesada-López T, et al. Oral administration of a new HRI activator as a new strategy to improve high-fat-diet-induced glucose intolerance, hepatic steatosis, and hypertriglyceridaemia through FGF21. Br J Pharmacol. 2019;176(13):2292–2305. doi: 10.1111/bph.14678
  • Tan M, Pujol E, Vazquez S, et al. Abstract 638: EPB-53 prevents NASH-HCC transition via regulation of SPHK1-S1P-HIPPO signaling and immune modulation in a murine model. Cancer Res. 2023;83(7_Supplement):638. doi: 10.1158/1538-7445.AM2023-638
  • Tang X, Xie X, Wang X, et al. The combination of piR-823 and eukaryotic initiation factor 3 B (EIF3B) activates hepatic stellate cells via upregulating TGF-β1 in liver fibrogenesis. Med Sci Monit. 2018;24:9151–9165. doi: 10.12659/MSM.914222
  • He P, Yu Z-J, Sun C-Y, et al. Knockdown of eIf3a attenuates the pro-fibrogenic response of hepatic stellate cells induced by TGF-β1. Cell Mol Biol (Noisy-le-Grand). 2016;62(6):107–111.
  • Gufler S, Seeboeck R, Schatz C, et al. The translational bridge between inflammation and Hepatocarcinogenesis. Cells. 2022;11(3):533. doi: 10.3390/cells11030533
  • Villamil FG, Gadano AC, Zingale F, et al. Fibrosis progression in maintenance liver transplant patients with hepatitis C recurrence: a randomised study of everolimus vs. calcineurin inhibitors. Liver Int. 2014;34(10):1513–1521. doi: 10.1111/liv.12416
  • Lu K, Fan Q, Zou X. Antisense oligonucleotide is a promising intervention for liver diseases. Front Pharmacol. 2022;13:1061842. doi: 10.3389/fphar.2022.1061842
  • Debacker AJ, Voutila J, Catley M, et al. Delivery of oligonucleotides to the liver with GalNAc: from research to registered therapeutic drug. Mol Ther. 2020;28(8):1759–1771. doi: 10.1016/j.ymthe.2020.06.015
  • Kim K-H, Park K-K. Small RNA- and DNA-based gene therapy for the treatment of liver cirrhosis, where we are? World J Gastroenterol. 2014;20(40):14696–14705. doi: 10.3748/wjg.v20.i40.14696
  • Yamaguchi K, Yang L, McCall S, et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology. 2007;45(6):1366–1374. doi: 10.1002/hep.21655
  • Nuñez-Durán E, Aghajan M, Amrutkar M, et al. Serine/threonine protein kinase 25 antisense oligonucleotide treatment reverses glucose intolerance, insulin resistance, and nonalcoholic fatty liver disease in mice. Hepatol Commun. 2018;2(1):69–83. doi: 10.1002/hep4.1128
  • Nie Q-H, Zhu C-L, Zhang Y-F, et al. Inhibitory effect of antisense oligonucleotide targeting TIMP-2 on immune-induced liver fibrosis. Dig Dis Sci. 2010;55(5):1286–1295. doi: 10.1007/s10620-009-0858-5
  • Nie QH, Cheng YQ, Xie YM, et al. Inhibiting effect of antisense oligonucleotides phosphorothioate on gene expression of TIMP-1 in rat liver fibrosis. World J Gastroenterol. 2001;7(3):363–369. doi: 10.3748/wjg.v7.i3.363
  • Horie S, Kitamura Y, Kawasaki H, et al. Inhibitory effects of antisense oligonucleotides on the expression of procollagen type III gene in mouse hepatic stellate cells transformed by simian virus 40. Pathol Int. 2000;50(12):937–944. doi: 10.1046/j.1440-1827.2000.01146.x
  • Liu W-B, Yang C-Q, Jiang W, et al. Inhibition on the production of collagen type I, III of activated hepatic stellate cells by antisense TIMP-1 recombinant plasmid. World J Gastroenterol. 2003;9(2):316–319. doi: 10.3748/wjg.v9.i2.316
  • Yu J, Zhu C, Wang X, et al. Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis. Sci Transl Med. 2021;13(599):eabe1692. doi: 10.1126/scitranslmed.abe1692
  • Tang M, Chen Y, Li B, et al. Therapeutic targeting of STAT3 with small interference RNAs and antisense oligonucleotides embedded exosomes in liver fibrosis. FASEB J. 2021;35(5):e21557. doi: 10.1096/fj.202002777RR
  • Mello CC, Conte D. Revealing the world of RNA interference. Nature. 2004;431(7006):338–342. doi: 10.1038/nature02872
  • Hu P-F, Xie W-F. Targeted RNA interference for hepatic fibrosis. Expert Opin Biol Ther. 2009;9(10):1305–1312. doi: 10.1517/14712590903213677
  • Ito S, Nagata K. Roles of the endoplasmic reticulum–resident, collagen-specific molecular chaperone Hsp47 in vertebrate cells and human disease. J Biol Chem. 2019;294(6):2133–2141. doi: 10.1074/jbc.TM118.002812
  • Lawitz EJ, Shevell DE, Tirucherai GS, et al. BMS-986263 in patients with advanced hepatic fibrosis: 36-week results from a randomized, placebo-controlled phase 2 trial. Hepatology. 2022;75(4):912–923. doi: 10.1002/hep.32181
  • Strnad P, Mandorfer M, Choudhury G, et al. Fazirsiran for liver disease associated with Alpha1-antitrypsin deficiency. N Engl J Med. 2022;387(6):514–524. doi: 10.1056/NEJMoa2205416
  • Morita K, Taketomi A, Shirabe K, et al. Clinical significance and potential of hepatic microRNA-122 expression in hepatitis C. Liver Int. 2011;31(4):474–484. doi: 10.1111/j.1478-3231.2010.02433.x
  • Lanford RE, Hildebrandt-Eriksen ES, Petri A, et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science. 2010;327(5962):198–201. doi: 10.1126/science.1178178
  • van der Ree MH, de Vree JM, Stelma F, et al. Safety, tolerability, and antiviral effect of RG-101 in patients with chronic hepatitis C: a phase 1B, double-blind, randomised controlled trial. Lancet. 2017;389(10070):709–717. doi: 10.1016/S0140-6736(16)31715-9
  • Stelma F, van der Ree MH, Sinnige MJ, et al. Immune phenotype and function of natural killer and T cells in chronic hepatitis C patients who received a single dose of anti-MicroRNA-122, RG-101. Hepatology. 2017;66(1):57–68. doi: 10.1002/hep.29148
  • Deng Y, Campbell F, Han K, et al. Randomized clinical trials towards a single-visit cure for chronic hepatitis C: oral GSK2878175 and injectable RG-101 in chronic hepatitis C patients and long-acting injectable GSK2878175 in healthy participants. J Viral Hepat. 2020;27(7):699–708. doi: 10.1111/jvh.13282
  • Hamasaki T, Suzuki H, Shirohzu H, et al. Efficacy of a novel class of RNA interference therapeutic agents. PLoS One. 2012;7(8):e42655. doi: 10.1371/journal.pone.0042655
  • Dalgaard LT, Sørensen AE, Hardikar AA, et al. The microRNA-29 family: role in metabolism and metabolic disease. Am J Physiol Cell Physiol. 2022;323(2):C367–C377. doi: 10.1152/ajpcell.00051.2022
  • Huang Y-H, Tiao M-M, Huang L-T, et al. Activation of mir-29a in activated hepatic stellate cells modulates its profibrogenic phenotype through inhibition of histone deacetylases 4. PLoS One. 2015;10(8):e0136453. doi: 10.1371/journal.pone.0136453
  • Liang C, Bu S, Fan X. Suppressive effect of microRNA-29b on hepatic stellate cell activation and its crosstalk with TGF-β1/Smad3. Cell Biochem Funct. 2016;34(5):326–333. doi: 10.1002/cbf.3193
  • Yang Y-L, Kuo H-C, Wang F-S, et al. MicroRNA-29a disrupts DNMT3b to ameliorate diet-induced non-alcoholic steatohepatitis in mice. Int J Mol Sci. 2019;20(6):1499. doi: 10.3390/ijms20061499
  • Trépo E, Valenti L. Update on NAFLD genetics: from new variants to the clinic. J Hepatol. 2020;72(6):1196–1209. doi: 10.1016/j.jhep.2020.02.020
  • Carlsson B, Lindén D, Brolén G, et al. Review article: the emerging role of genetics in precision medicine for patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2020;51(12):1305–1320. doi: 10.1111/apt.15738
  • Chen Y, Du X, Kuppa A, et al. Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease. Nat Genet. 2023;55(10):1640–1650. doi: 10.1038/s41588-023-01497-6
  • Helsley RN, Varadharajan V, Brown AL, et al. Obesity-linked suppression of membrane-bound O-acyltransferase 7 (MBOAT7) drives non-alcoholic fatty liver disease. Elife. 2019;8:e49882. doi: 10.7554/eLife.49882
  • Varadharajan V, Ramachandiran L, Massey WJ, et al. Membrane bound O-Acyltransferase 7 (MBOAT7) shapes lysosomal lipid homeostasis and function to control alcohol-associated liver injury. bioRxiv. 2023 Sep 26;559533. doi: 10.1101/2023.09.26.559533
  • Fuchs CD, Radun R, Dixon ED, et al. Hepatocyte-specific deletion of adipose triglyceride lipase (adipose triglyceride lipase/patatin-like phospholipase domain containing 2) ameliorates dietary induced steatohepatitis in mice. Hepatology. 2022;75(1):125–139. doi: 10.1002/hep.32112
  • Schwartz BE, Rajagopal V, Smith C, et al. Discovery and targeting of the signaling controls of PNPLA3 to effectively reduce transcription, expression, and function in pre-clinical NAFLD/NASH settings. Cells. 2020;9(10):2247. doi: 10.3390/cells9102247
  • Liu S, Murakami E, Nakahara T, et al. In vitro analysis of hepatic stellate cell activation influenced by transmembrane 6 superfamily 2 polymorphism. Mol Med Rep. 2021;23(1):16. doi: 10.3892/mmr.2020.11654
  • Cherubini A, Casirati E, Tomasi M, et al. PNPLA3 as a therapeutic target for fatty liver disease: the evidence to date. Expert Opin Ther Targets. 2021;25(12):1033–1043. doi: 10.1080/14728222.2021.2018418
  • Lindén D, Ahnmark A, Pingitore P, et al. Pnpla3 silencing with antisense oligonucleotides ameliorates nonalcoholic steatohepatitis and fibrosis in Pnpla3 I148M knock-in mice. Mol Metab. 2019;22:49–61. doi: 10.1016/j.molmet.2019.01.013
  • Smith CR, Powell RG, Mikolajczak KL. The genus cephalotaxus: source of homoharringtonine and related anticancer alkaloids. Cancer Treat Rep. 1976;60(8):1157–1170.
  • Fresno M, Jiménez A, Vázquez D. Inhibition of translation in eukaryotic systems by harringtonine. Eur J Biochem. 1977;72(2):323–330. doi: 10.1111/j.1432-1033.1977.tb11256.x
  • Tujebajeva RM, Graifer DM, Karpova GG, et al. Alkaloid homoharringtonine inhibits polypeptide chain elongation on human ribosomes on the step of peptide bond formation. FEBS Lett. 1989;257(2):254–256. doi: 10.1016/0014-5793(89)81546-7
  • Alvandi F, Kwitkowski VE, Ko C-W, et al. U.S. Food and drug administration approval summary: omacetaxine mepesuccinate as treatment for chronic myeloid leukemia. Oncology. 2014;19(1):94–99. doi: 10.1634/theoncologist.2013-0077
  • Yang C, Zhang H, Chen M, et al. A survey of optimal strategy for signature-based drug repositioning and an application to liver cancer. Elife. 2022;11:e71880. doi: 10.7554/eLife.71880
  • Yerukala Sathipati S, Tsai M-J, Shukla SK, et al. Artificial intelligence-driven pan-cancer analysis reveals miRNA signatures for cancer stage prediction. HGG Adv. 2023;4(3):100190. doi: 10.1016/j.xhgg.2023.100190
  • Sun J, Ru J, Ramos-Mucci L, et al. DeepsmirUD: prediction of regulatory effects on microRNA expression mediated by small molecules using deep learning. Int J Mol Sci. 2023;24(3):1878. doi: 10.3390/ijms24031878
  • Li J, Lin H, Wang Y, et al. Prediction of potential small molecule-miRNA associations based on heterogeneous network representation learning. Front Genet. 2022;13:1079053. doi: 10.3389/fgene.2022.1079053

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.