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独特的saRNA新药发现平台

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RNA激活技术

“RNA激活”（RNA activation， 简称RNAa）是一种新的生物学现象和基因调控机制，由中美瑞康公司创始人李龙承于2006年在世界上首次发现并命名。该机制能够利用小分子RNA（也称小激活RNA，saRNA）实现对体内基因的特异性和长效激活，是生命健康领域应用前景十分广阔并已进入临床验证的前沿性和颠覆性技术，将为无数疾病包括很多目前尚缺乏治疗方法的疾病的治疗带来新的希望。

RNA激活的技术优势

RNA激活利用短的非编码寡核苷酸来靶向和上调内源基因的转录，从而恢复蛋白质的天然功能。与传统的靶向药或者基因治疗相比，它具有前所未有的技术优势：

  1. 具有几乎无限的靶基因，为传统靶向治疗（小分子、单抗、RNAi等）不能治疗的疾病提供治疗机会，拥有无限可能的应用；

  2. 忠实地恢复基因的天然功能；

  3. 持久激活靶基因；

  4. 不改变基因组；

  5. 利用已经成熟的siRNA药物化学及给药技术加速saRNA药的开发；

  6. 通过进一步优化先导saRNA，可以提高其成药性及转录激活效率

我们的方法

很多疾病的发生是细胞内某一个或者多个有益蛋白表达不足或者缺乏而引起，包括几乎所有常见病（肿瘤、心血管代谢病、自身免疫病等）和少见罕见病（如单等位突变而导致的单基因遗传病）。补充这些有益（治疗性）蛋白则可以达到治疗目的。目前仅有极少数疾病（如糖尿病）可以通过直接补充蛋白质（如胰岛素）而获益。传统的基因治疗为另外一种基因补充疗法，但基因治疗由于需要利用外源性的遗传物质（如病毒载体），在人体使用有很大的安全隐患。

在过去十年中，寡核苷酸（也称小核酸）作为一种重要的新型医药品种应运而生。寡核苷酸不编码任何外源基因，其活性完全取决于其与靶基因碱基互补配对。然而，几乎所有基于寡核苷酸的药物（如siRNA和反义核酸）都是通过沉默基因表达而只能达到对靶蛋白的抑制作用。

中美瑞康的新药研发平台基于RNA激活技术，即利用寡核苷酸来特异性靶向和激活--而不是沉默--治疗性基因的表达。因此，中美瑞康可以利用已经成熟的siRNA药物化学及给药技术来加速我们的药物研发进程。此外，RNA激活拥有增强靶基因转录的独特能力，可提供一种更天然的基因补充疗法。RNA激活还可以恢复沉默基因的表达，而这些基因在以前被认为是尚无药物可及（undruggable）的靶点。

RNAa 时间轴

  • 1969

    Britten和Davidson提出“RNA激活子"（RNA activator)假说 (Britten and Davidson. Science 1969)

  • 2006

    RNA激活现象被发现 – 李龙承等（加州大学旧金山分校）在人细胞首次发现小RNA-Ago介导的转录/表观激活现象，并命名该现象为RNAa (Li et al. PNAS 2006)

  • 2007

    Janowski等（得克萨斯大学）报道人细胞的RNAa现象 (Janowski et al. Nature Struct Biol 2007)

  • 2008

    Place等首次报道miRNA介导的RNA激活 (Place et al. PNAS 2008)

  • 2009

    RNA激活首次用于实验性疾病治疗 – Turunen等报道在体（in vivo) RNA激活， 首次开展利用RNAa激活治疗疾病的临床前研究，并提出“表观基因治疗”的概念 (Turunen et al. Circ Res 2009)

  • 2010

    Huang等报道RNA激活在哺乳类细胞的保守性 (Huang et al. PLoS One 2010)

  • 2012

    Huang等发现miRNA介导的RNA激活在细胞生理条件发挥作用，并可能参与癌变过程 (Huang et al. NAR 2012)

  • 2012

    李龙承在UCSF的实验室与Alnylam制药公司合作完成两项saRNA治疗肿瘤（前列腺癌及膀胱癌）的临床前研究 (Place et al. Mol Ther-Nucleic Acids 2012; Kang et al. Cancer Res 2013)

  • 2013

    Craig Mello（因发现RNA干扰而获得诺贝尔奖）实验室首次报道线虫的RNA激活现象 (Seth et al. Dev Cell 2013)

  • 2013

    Frank Slack实验室报道线虫在体miRNA介导的RNAa--lin-4 （历史上第一个被发现的miRNA）通过靶向自身启动子而形成正反馈环路 (Turner et al. Cell Cycle 2014)

  • 2014

    MiNA Therapeutics （英国）从加州大学旧金山分校（UCSF）获得李龙承实验室有关RNA激活技术开发权益 (相关新闻)  

  • 2016

    RNA激活技术首次进入临床验证 – 由英国MiNA Therapeutics公司开发的世界上第一个saRNA药进入临床实验，用于肝癌治疗 (NIH clinical trial number: NCT02716012)

  • 2016

    李龙承实验室报道解析RITA (RNA介导的转录激活）复合物 (Portnoy et al. Cell Res 2016)； 北京大学梁子才实验室报道对RNA激活分子机制的新认识 (Meng et al. Nucleic Acids Res 2016)

  • 2017

    中美瑞康于2016年9月注册成立，于2017年6月正式启动

  • 2021

    中美瑞康完成价值1.2亿元人民币A轮融资

知识产权

借助中美瑞康功能强大的高通量发现引擎，我们可以迅速发现任何靶基因的多个活性saRNA分子。同时结合我们的精确的生物信息学搜索引擎来识别可触发基因激活的靶序列。这两个过程都不依赖于靶序列上非编码RNA转录或染色质结构的信息。我们正在针对大量的治疗性基因筛选成千上万的活性saRNA分子，以扩大我们的知识产权池，并积极推动我们的先导化合物进入I期临床试验。

学术论文与报告

  1. Yong-Li Zhang, Moorim Kang, Jian-Cheng Wu, Meng-Yao Xie, Ruo-Yan Xue, Qi Tang, Hua Yang & Long-Cheng Li (2022) Small activating RNA activation of ATOH1 promotes regeneration of human inner ear hair cells. Bioengineered, 13:3, 6729-6739, DOI: 10.1080/21655979.2022.2045835
  2. Kang MR, Park KH, Lee CW, Lee MY, Han SB, Li LC, Kang JS. Small activating RNA induced expression of VHL gene in renal cell carcinoma. Int J Biochem Cell Biol. 2018 Feb: S1357-2725(18)30030-X. 
  3. Portnoy V, Lin SH, Li KH, Burlingame A, Hu ZH, Li H, Li LC. saRNA-guided Ago2 targets the RITA complex to promoters to stimulate transcription. Cell Res. 2016 Feb 23.
  4. Wang J, Place RF, Portnoy V, Huang V, Kang MR, Kosaka M, Ho MK, Li LC. Inducing gene expression by targeting promoter sequences using small activating RNAs. J Biol Methods. 2015 Mar 11; 2(1).
  5. Wang J, Huang V, Ye L, Bárcena A, Lin G, Lue TF and Li LC. Identification of small activating RNAs that enhance endogenous OCT4 expression in human mesenchymal stem cells. Stem Cell Dev 2014 Sep 18.
  6. Wang X, Wang J, Huang V, Place RF, and Li LC. Induction of NANOG expression by targeting promoter sequence with small activating RNA antagonizes retinoic acid-induced differentiation. Biochem J 2012 May 1; 443(3):821-8.
  7. Wang T, Li M, Yuan H, Zhan Y, Xu H, Wang S, Yang W, Liu J and Li LC. Small activating RNA-guided iNOS up-regulation improves erectile function of diabetic rats. J Urol 2013 Aug; 190(2):790-8.
  8. Kosaka M, Kang MR, Yang G and Li LC. Targeted p21 WAF1/CIP1 activation by RNAa inhibits hepatocellular carcinoma cells. Nucleic Acid Ther 2012 2012 Oct; 22(5):335-43.
  9. Kang MR, Yang G, Place RF, Charisse K, Epstein-Barash H, Manoharan H and LI LC. Intravesical delivery of small activating RNA formulated into lipid nanoparticles inhibits orthotopic bladder tumor growth. Cancer Res 2012 Oct 1;72(19):5069-79.  
  10. Ren S, Kang MR, Wang J, Huang V, Place RF, Sun Y, Li LC. Targeted induction of endogenous NKX3-1 by small activating RNA inhibits prostate tumor growth. Prostate. Oct; 73(14):1591-601.
  11. Place RF, Wang J, Noonan E, Meyers R, Manoharan M, Charisse K, Duncan R, Huang V, Wang X and Li LC. Formulation of small activating RNA into lipidoid nanoparticles inhibits xenograft prostate tumor growth by inducing p21 expression. Molecular Therapy - Nucleic Acids 2012; e15.
  12. Chen Z, Place RF, Jia ZJ, Pookot D, Dahiya R, Li LC. Antitumor effect of dsRNA-induced p21WAF1/CIP1 gene activation in human bladder cancer cells. Mol Cancer Ther. 2008 Mar;7(3):698-703.
  13. Place RF, Li LC, Pookot D, Noonan EJ, Dahiya R. MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1608-13. Epub 2008 Jan 28.
  14. Li LC, Okino ST, Zhao H, Pokot D, Place RF, Dahiya R. Small double-stranded RNAs induce transcriptional activation in human cells. Proc Natl Acad Sci USA. 2006 Nov 14;103(46):17337-17342.
  1. Janowski BA, Younger ST, Hardy DB, Ram R, Huffman KE, Corey DR. Activating gene expression in mammalian cells with promoter-targeted duplex RNAs. Nat Chem Biol. 2007;3:166-73.
  2. Yue X, Schwartz JC, Chu Y, Younger ST, Gagnon KT, Elbashir S, et al. Transcriptional regulation by small RNAs at sequences downstream from 3' gene termini. Nat Chem Biol. 2010;6:621-9.
  3. Turunen MP, Lehtola T, Heinonen SE, Assefa GS, Korpisalo P, Girnary R, et al. Efficient regulation of VEGF expression by promoter-targeted lentiviral shRNAs based on epigenetic mechanism: a novel example of epigenetherapy. Circ Res. 2009;105:604-9.
  4. Turner MJ, Jiao AL, Slack FJ. Autoregulation of lin-4 microRNA transcription by RNA activation (RNAa) in C. elegans. Cell Cycle. 2014;13:772-81.
  5. Chu Y, Yue X, Younger ST, Janowski BA, Corey DR. Involvement of argonaute proteins in gene silencing and activation by RNAs complementary to a non-coding transcript at the progesterone receptor promoter. Nucleic Acids Res. 2010;38:7736-48.
  6. Meng X, Jiang Q, Chang N, Wang X, Liu C, Xiong J, et al. Small activating RNA binds to the genomic target site in a seed-region-dependent manner. Nucleic Acids Res. 2016;44:2274-82.
  7. Hu J, Chen Z, Xia D, Wu J, Xu H, Ye ZQ. Promoter-associated small double-stranded RNA interacts with heterogeneous nuclear ribonucleoprotein A2/B1 to induce transcriptional activation. Biochem J. 2012;447:407-16.
  8. Chaluvally-Raghavan P, Jeong KJ, Pradeep S, Silva AM, Yu S, Liu W, et al. Direct Upregulation of STAT3 by MicroRNA-551b-3p Deregulates Growth and Metastasis of Ovarian Cancer. Cell Rep. 2016;15:1493-504.
  9. Matsui M, Chu Y, Zhang H, Gagnon KT, Shaikh S, Kuchimanchi S, et al. Promoter RNA links transcriptional regulation of inflammatory pathway genes. Nucleic Acids Res. 2013;41:10086-109.
  10. Matsui M, Sakurai F, Elbashir S, Foster DJ, Manoharan M, Corey DR. Activation of LDL receptor expression by small RNAs complementary to a noncoding transcript that overlaps the LDLR promoter. Chem Biol. 2010;17:1344-55.
  11. Lopez P, Wagner KD, Hofman P, Van Obberghen E. RNA Activation of the Vascular Endothelial Growth Factor Gene (VEGF) Promoter by Double-Stranded RNA and Hypoxia: Role of Noncoding VEGF Promoter Transcripts. Mol Cell Biol. 2016;36:1480-93.
  12. Turunen MP, Husso T, Musthafa H, Laidinen S, Dragneva G, Laham-Karam N, et al. Epigenetic upregulation of endogenous VEGF-A reduces myocardial infarct size in mice. PLoS One. 2014;9:e89979.
  13. Reebye V, Saetrom P, Mintz PJ, Rossi JJ, Kasahara N, Nteliopoulos G, et al. A Short-activating RNA Oligonucleotide Targeting the Islet beta-cell Transcriptional Factor MafA in CD34(+) Cells. Mol Ther Nucleic Acids. 2013;2:e97.
  14. Reebye V, Saetrom P, Mintz PJ, Huang KW, Swiderski P, Peng L, et al. Novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo. Hepatology. 2014;59:216-27.
  15. Yoon S, Huang KW, Reebye V, Mintz P, Tien YW, Lai HS, et al. Targeted Delivery of C/EBPalpha -saRNA by Pancreatic Ductal Adenocarcinoma-specific RNA Aptamers Inhibits Tumor Growth In Vivo. Mol Ther. 2016.
  16. Li C, Jiang W, Hu Q, Li LC, Dong L, Chen R, et al. Enhancing DPYSL3 gene expression via a promoter-targeted small activating RNA approach suppresses cancer cell motility and metastasis. Oncotarget. 2016;7:22893-910.
  17. Wang LL, Feng CL, Zheng WS, Huang S, Zhang WX, Wu HN, et al. Tumor-selective lipopolyplex encapsulated small active RNA hampers colorectal cancer growth in vitro and in orthotopic murine. Biomaterials. 2017;141:13-28.
  18. Harris EA, Buzina A, Moffat J, McMillen DR. Design and Experimental Validation of Small Activating RNAs Targeting an Exogenous Promoter in Human Cells. . ACS Synth Biol. 2017 Apr 21;6(4):628-637. doi: 10.1021/acssynbio.6b00125. Epub 2017 Jan 17. PubMed PMID: 28033709.
  19. Voutila J, Reebye V, Roberts TC, Protopapa P, Andrikakou P, Blakey DC, Habib R, Huber H, Saetrom P, Rossi JJ, Habib NA. Development and Mechanism of Small Activating RNA Targeting CEBPA, a Novel Therapeutic in Clinical Trials for Liver Cancer. Mol Ther. 2017 Dec 6;25(12):2705-2714. doi: 10.1016/j.ymthe.2017.07.018. Epub 2017 Aug 4. PubMed PMID: 28882451.
  20. Zhang Y, Liu W, Chen Y, Liu J, Wu K, Su L, Zhang W, Jiang Y, Zhang X, Zhang Y, Liu C, Tao L, Liu B, Zhang H. A Cellular MicroRNA Facilitates Regulatory T Lymphocyte Development by Targeting the FOXP3 Promoter TATA-Box Motif. J Immunol. 2017 Dec 27. pii: ji1700196. doi: 10.4049/jimmunol.1700196. [Epub ahead of print] PubMed PMID: 29282311.
  21. Ohno SI, Oikawa K, Tsurui T, Harada Y, Ono K, Tateishi M, Mirza A, Takanashi M, Kanekura K, Nagase K, Shimada Y. Nuclear microRNAs release paused Pol II via the DDX21-CDK9 complex. Cell Reports. 2022 Apr 12;39(2):110673.

  1. Van Simaeys, D., De La Fuente, A., Zilio, S. et al. RNA aptamers specific for transmembrane p24 trafficking protein 6 and Clusterin for the targeted delivery of imaging reagents and RNA therapeutics to human β cells. Nat Commun 13, 1815 (2022). https://doi.org/10.1038/s41467-022-29377-3

  2. Reebye V, Huang KW, Lin V, Jarvis S, Cutilas P, et al. Gene activation of CEBPA using saRNA: preclinical studies of the first in human saRNA drug candidate for liver cancer. Oncogene. 2018 Jun;37(24):3216-3228. doi: 10.1038/s41388-018-0126-2.

  3. Zeng T, Duan X, Zhu W, Liu Y, Wu W, Zeng G. SaRNA-mediated activation of TRPV5 reduces renal calcium oxalate deposition in rat via decreasing urinary calcium excretion. Urolithiasis. 2017 Aug 3.
  4. Wang LL, Feng CL, Zheng WS, Huang S, Zhang WX, Wu HN, Zhan Y, Han YX, Wu S,Jiang JD. Tumor-selective lipopolyplex encapsulated small active RNA hampers colorectal cancer growth in vitro and in orthotopic murine. Biomaterials. 2017Oct;141:13-28.
  5. Fimiani C, Goina E, Su Q, Gao G, Mallamaci A. RNA activation of haploinsufficient Foxg1 gene in murine neocortex. Sci Rep. 2016 Dec 20;6:39311.
  6. Huan H, Wen X, Chen X, Wu L, Liu W, Habib NA, Bie P, Xia F. C/EBPα Short-Activating RNA Suppresses Metastasis of Hepatocellular Carcinoma through Inhibiting EGFR/β-Catenin Signaling Mediated EMT. PLoS One. 2016 Apr6;11(4):e0153117.  
  7. Li C, Jiang W, Hu Q, Li LC, Dong L, Chen R, Zhang Y, Tang Y, Thrasher JB, Liu CB, Li B. Enhancing DPYSL3 gene expression via a promoter-targeted small activating RNA approach suppresses cancer cell motility and metastasis. Oncotarget. 2016 Apr 19;7(16):22893-910.  
  8. Wang C, Ge Q, Zhang Q, Chen Z, Hu J, Li F, Ye Z. Targeted p53 activation by saRNA suppresses human bladder cancer cells growth and metastasis. J Exp Clin Cancer Res. 2016 Mar 25;35:53.  
  9. Yoon S, Huang KW, Reebye V, Mintz P, Tien YW, Lai HS, Sætrom P, Reccia I, Swiderski P, Armstrong B, Jozwiak A, Spalding D, Jiao L, Habib N, Rossi JJ. Targeted Delivery of C/EBPα -saRNA by Pancreatic Ductal Adenocarcinoma-specific RNA Aptamers Inhibits Tumor Growth In Vivo. Mol Ther. 2016 Jun;24(6):1106-1116.
  10. Turunen MP, Husso T, Musthafa H, Laidinen S, Dragneva G, Laham-Karam N, Honkanen S, Paakinaho A, Laakkonen JP, Gao E, Vihinen-Ranta M, Liimatainen T, Ylä-Herttuala S. Epigenetic upregulation of endogenous VEGF-A reduces myocardial infarct size in mice. PLoS One. 2014 Feb 26;9(2):e89979.
  11. Ren S, Kang MR, Wang J, Huang V, Place RF, Sun Y, Li LC. Targeted induction of endogenous NKX3-1 by small activating RNA inhibits prostate tumor growth. Prostate. 2013 Oct;73(14):1591-601.  
  12. Wang T, Li M, Yuan H, Zhan Y, Xu H, Wang S, Yang W, Liu J, Ye Z, Li LC. saRNA guided iNOS up-regulation improves erectile function of diabetic rats. J Urol.2013 Aug;190(2):790-8.
  13. Zhang Z, Wang Z, Liu X, Wang J, Li F, Li C, Shan B. Up-regulation of p21WAF1/CIP1 by small activating RNA inhibits the in vitro and in vivo growth of pancreatic cancer cells. Tumori. 2012 Nov;98(6):804-11.
  14. Place RF, Wang J, Noonan EJ, Meyers R, Manoharan M, Charisse K, Duncan R, Huang V, Wang X, Li LC. Formulation of Small Activating RNA Into Lipidoid Nanoparticles Inhibits Xenograft Prostate Tumor Growth by Inducing p21Expression. Mol Ther Nucleic Acids. 2012 Mar 27;1:e15.
  15. Kang MR, Yang G, Place RF, Charisse K, Epstein-Barash H, Manoharan M, Li LC. Intravesical delivery of small activating RNA formulated into lipid nanoparticles inhibits orthotopic bladder tumor growth. Cancer Res. 2012 Oct 1;72(19):5069-79.
  16. Turunen MP, Lehtola T, Heinonen SE, Assefa GS, Korpisalo P, Girnary R, Glass CK, Väisänen S, Ylä-Herttuala S. Efficient regulation of VEGF expression by promoter-targeted lentiviral shRNAs based on epigenetic mechanism: a novel example of epigenetherapy. Circ Res. 2009 Sep 11;105(6):604-9.

综述

  1. Kwok A, Raulf N, Habib N. Developing small activating RNA as a therapeutic: current challenges and promises. Ther Deliv. 2019 Mar;10(3):151-164. full-text paper
  2. Setten RL, Rossi JJ, Han SP. The current state and future directions of RNAi-based therapeutics. Nat Rev Drug Discov. 2019 Mar 7. doi: 10.1038/s41573-019-0017-4
  3. Li SM, Hu J. Small activating RNAs: towards development of new therapeutic agents and clinical treatments. Curr Pharm Biotechnol. 2018 Aug 2. doi: 10.2174/1389201019666180802145134.
  4. Setten RL, Lightfoot HL, Habib NA, Rossi JJ. Development of MTL-CEBPA: Small Activating RNA Drug for Hepatocellular Carcinoma. Curr Pharm Biotechnol. 2018 Jun 10. doi: 10.2174/1389201019666180611093428.
  5. Zhou LY, He ZY, Xu T, Wei YQ. Current Advances in Small Activating RNAs for Gene Therapy: Principles, Applications and Challenges. Curr Gene Ther. 2018 Jun 19. doi: 10.2174/1566523218666180619155018.
  6. Vaschetto LM. miRNA activation is an endogenous gene expression pathway. RNA Biol. 2018 Apr 3:1-3.
  7. Li LC. Small RNA-Guided Transcriptional Gene Activation (RNAa) in Mammalian Cells. Adv Exp Med Biol. 2017;983:1-20.
  8. Kang MR, Li G, Pan T, Xing JC, Li LC. Development of therapeutic dsP21-322 for Cancer Treatment. Adv Exp Med Biol. 2017;983:217-229.
  9. Corey DR. RNA-Mediated Gene Activation: Identifying a Candidate RNA for Preclinical Development.Adv Exp Med Biol. 2017;983:161-171.
  10. Mallamaci A. Enhancing Neuronogenesis and Counteracting Neuropathogenic Gene Haploinsufficiencies by RNA Gene Activation. Adv Exp Med Biol. 2017;983:23-39.
  11. Vaschetto LM. RNA Activation: A Diamond in the Rough for Genome Engineers. J Cell Biochem. 2017 Jun 21.
  12. Gustincich S, Zucchelli S, Mallamaci A. The Yin and Yang of nucleic acid-based therapy in the brain. Prog Neurobiol. 2017 Aug;155:194-211.
  13. Guo D, Barry L, Lin SS, Huang V, Li LC. RNAa in action: from the exception to the norm. RNA Biol. 2014;11(10):1221-5.
  14. Zheng L, Wang L, Gan J, Zhang H. RNA activation: promise as a new weapon against cancer. Cancer Lett. 2014 Dec 1;355(1):18-24.
  15. Jiao AL, Slack FJ. RNA-mediated gene activation. Epigenetics. 2014 Jan;9(1):27-36.
  16. Esquela-Kerscher A. The lin-4 microRNA: The ultimate micromanager. Cell Cycle. 2014;13(7):1060-1.
  17. Li LC. Chromatin remodeling by the small RNA machinery in mammalian cells. Epigenetics. 2014 Jan;9(1):45-52.
  18. Portnoy V, Huang V, Place RF, Li LC. Small RNA and transcriptional upregulation. Wiley Interdiscip Rev RNA. 2011 Sep-Oct;2(5):748-60.
  19. Janowski BA, Corey DR. Minireview: Switching on progesterone receptor expression with duplex RNA. Mol Endocrinol. 2010 Dec;24(12):2243-52.
  20. Pushparaj PN, Aarthi JJ, Kumar SD, Manikandan J. RNAi and RNAa--the yin and yang of RNAome. Bioinformation. 2008 Jan 11;2(6):235-7.
  21. Rossi JJ. Transcriptional activation by small RNA duplexes.Nature Chem Biol. 2007 March;3(3):136-37.

新闻与评述

  1. Garber K. Small RNAs reveal an activating side. Science 2006 Nov 3;313:741-42.
  2. How to get your genes switched on. New Scientist 2006 Nov 18:20.
  3. Elizabeth M. Activating gene expression. Science. STKE 2006 Nov 21;362:392.
  4. Karberg S. Positive Interferenz. Süddeutsche Zeitung 2006 Nov 8.
  5. Holmes B. Switched on. New Scientist 2007 April 7:42-45.
  6. Okoye SE. Scientists' new genes discovery may be manipulated to disable any disease. Guardian 2007 Jul 5.
  7. Check E. Hitting the on switch. Nature 2007 Aug 23;448:885-58. Read the article
  8. Dolgin E. Now showing: RNA Activation. The Scientist 2009;23(5):34-39.
  9. Payton S. Intravesical RNA activation—a new treatment concept. Nature Reviews Urol 2012 August 28.
  10. Oligonucleotide Therapeutics Society. Perspectives on current science – June 2016.

研究引擎

内容即将发布。

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