核酸药物是指可用于治疗疾病的核酸本身或与之密切相关的化合物,包括天然核苷酸和经化学修饰的核苷酸。虽然核酸药物的类型多种多样,但它们都有一个共同的作用机制,通过Watson-Crick碱基互补配对机制特异性识别内源性核酸序列,从而发挥作用[1]。除基因治疗以外,用于治疗的核酸还可通过抑制DNA或RNA的表达,从而抑制与疾病相关的异常蛋白表达,且不影响其他蛋白的表达[2]。与抗体药物相比,核酸药物表现出超过抗体药物的功效和安全性,又因相对较小的分子量而利于药企批量生产。这些特点,使核酸药物有望应用于以前难以治疗的癌症和遗传性疾病,以及流感等病毒感染引起的疾病。
图4 LC-MS/MS检测核酸药物的样品制备方法[27]
图5 SplintR qPCR法定量检测不同类型的ASOs[28]
图6 Patisiran 临床II期MAD试验ALN-18328 (A, B), DLin-MC3-DMA (C, D), and PEG2000-C-DMG (E, F) 的血浆样品浓度检测[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.
北京阳光德美医药科技有限公司是一家集大/小分子药物临床前/临床PK/PD服务于一体的综合性研究平台,可提供全方位的药代动力学-药效学和GLP生物分析服务,专注于解决
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