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核酸藥物是指可用于治療疾病的核酸本身或與之密切相關(guān)的化合物，包括天然核苷酸和經(jīng)化學(xué)修飾的核苷酸。雖然核酸藥物的類型多種多樣，但它們都有一個(gè)共同的作用機(jī)制，通過(guò)Watson-Crick堿基互補(bǔ)配對(duì)機(jī)制特異性識(shí)別內(nèi)源性核酸序列，從而發(fā)揮作用[1]。除基因治療以外，用于治療的核酸還可通過(guò)抑制DNA或RNA的表達(dá)，從而抑制與疾病相關(guān)的異常蛋白表達(dá)，且不影響其他蛋白的表達(dá)[2]。與抗體藥物相比，核酸藥物表現(xiàn)出超過(guò)抗體藥物的功效和安全性，又因相對(duì)較小的分子量而利于藥企批量生產(chǎn)。這些特點(diǎn)，使核酸藥物有望應(yīng)用于以前難以治療的癌癥和遺傳性疾病，以及流感等病毒感染引起的疾病。     圖4 LC-MS/MS檢測(cè)核酸藥物的樣品制備方法[27]      圖5 SplintR qPCR法定量檢測(cè)不同類型的ASOs[28]  圖6 Patisiran 臨床II期MAD試驗(yàn)ALN-18328 (A, B), DLin-MC3-DMA (C, D), and PEG2000-C-DMG (E, F) 的血漿樣品濃度檢測(cè)[29] [1] Cavagnari BM. Gene therapy: nucleic acids as drugs. Action, mechanisms and delivery into the cell[J]. Arch Argent Pediatr 2011; 109: 237–44. [2] Wraight CJ, White PJ. Antisense oligonucleotides in cutaneous therapy[J]. Pharmacol Ther 2001; 90: 89–104. [3] Sridharan K , Gogtay N J . Therapeutic Nucleic Acids: Current clinical status[J]. British Journal of Clinical Pharmacology, 2016, 82(3):659-672. [4] Kole R, Krainer AR, Altman S. RNA therapeutics: beyond RNA interference and antisense oligonucleotides[J]. Nat Rev Drug Discov 2012; 11: 125–40. [5] Andronescu M, Zhang ZC, Condon A. Secondary structure prediction of interacting RNA molecules[J]. Mol Biol 2005; 345: 987–1001. [68] Sun H, Zhu X, Lu PY, et al. Oligonucleotide aptamers: tools for targeted cancer therapy[J]. Mol Ther Nucleic Acids 2014; 3: e182. [7] Lee JM, Yoon TJ, Cho YS. Recent developments in nanoparticlebased siRNA delivery for cancer therapy[J]. BioMed Res Int 2013; 2013: 782041. [8] Elbashir SM, Harborth J, Lendeckel W, et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells[J]. Nature 2001; 411: 494–8. [9] Bo Hu, Yuhua Weng, Xin‐Hua Xia, et al. Clinical advances of siRNA therapeutics[J]. Gene Med. 2019;21:e3097. [10]Almeida ML, Reis RM, Calin GA. MicroRNa history: discovery, recent applications, and next frontiers[J]. Mutat Res Fund Mol Mech Mutagen 2011; 717: 1–8. [11]Bader AG. miR-34 – a microRNA replacement therapy is headed to the clinic[J]. Front Genet 2012; 3: 120. [12] Mendell JT, Olson EN. MicroRNAs in stress signaling and human disease[J]. Cell 2012; 148: 1172–87. [13] Ottosen S, Parsley TB, Yang L, et al. In vitro antiviral activity and preclinical and clinical resistance profile of Miravirsen, a novel anti-hepatitis C virus therapeutic targeting the human factor miR-122[J]. Antimicrob Agents Chemother 2015; 59: 599–608. [14] Lorio MV, Croce CM. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review[J]. EMBO Mol Med 2012; 4: 143–59. [15] Germer K, Leonard M, Zhang X. RNA aptamers and their therapeutic and diagnostic applications. [J] Int J Biochem Mol Biol 2013; 4: 27–40. [16] Lee JW, Kim HJ, Heo K. Therapeutic aptamers: developmental potential as anticancer drugs[J]. BMB Rep 2015; 48: 234–7. [17] Abera G, Berhanu G, Tekewe A. Ribozymes: nucleic acid enzymes with potential pharmaceutical applications: a review[J]. Pharmacophore. 2012; 3: 164–78. [18] Puerta-Fernández E, Romero-López C, Barroso-delJesus A, et al. Ribozymes: recent advances in the development of RNA tools[J]. FEMS Microbiol Rev 2003; 27: 75–97. [19] Elsa C. Kuijper1, Atze J. Bergsma, W.W.M. Pim Pijnappel, et al. Opportunities and challenges for antisense oligonucleotide therapies[J]. Inherit Metab Dis. 2020;1–16. [20] Weng Y, Huang Q, Li C, et al. Improved Nucleic Acid Therapy with Advanced Nanoscale Biotechnology[J]. Mol. Ther.–Nucleic Acids 2020, 19, 581? 601. [21] Crooke ST. Molecular mechanisms of antisense oligonucleotides[J]. Nucl Acid Ther. 2017;27:70-77. [22] Jarver P, O'Donovan L, Gait MJ. A chemical view of oligonucleotides for exon skipping and related drug applications[J]. Nucl Acid Ther. 2014;24:37-47. [23] Eckstein F. Phosphorothioates, essential components of therapeutic oligonucleotides[J]. Nucl Acid Ther. 2014;24:374-387. [24] Hartmann G. Nucleic acid immunity[J]. Adv Immunol. 2017;133: 121-169. [25] Martinez T, Jimenez AI, Paneda C. Short-interference RNAs: becoming medicines[J]. EXCLI J 2015; 14: 714–46. [26] Lucas-Samuel S, Ferry N, Trouvin JH. Overview of the regulatory oversight implemented by the French regulatory authorities for the clinical investigation of gene therapy and cell therapy products[J]. Adv Exp Med Biol 2015; 871: 73–85. [27] Sutton J M , Kim J , Zahar N , et al. Bioanalysis and biotransformation of oligonucleotide therapeutics by liquid chromatography‐mass spectrometry [J]. Mass Spectrometry Reviews, 2020. [28] Shin M , Krishnamurthy P M , Watts J K . Quantification of Antisense Oligonucleotides by Splint Ligation and Quantitative Polymerase Chain Reaction. 2021. [29] Zhang X, Goel V, Attarwala H, et al. Patisiran pharmacokinetics, pharmacodynamics, and exposure-response analyses in the phase 3 APOLLO trial in patients with hereditary transthyretin-mediated (hATTR) amyloidosis[J]. Clin Pharmacol. 2019.
北京陽(yáng)光德美醫(yī)藥科技有限公司是一家集大/小分子藥物臨床前/臨床PK/PD服務(wù)于一體的綜合性研究平臺(tái)，可提供全方位的藥代動(dòng)力學(xué)-藥效學(xué)和GLP生物分析服務(wù)，專注于解決 |
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