下一代免疫&基因疗法突破口：小核酸药物

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Author:华讯知识产权
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Time of issue:2019-05-17 18:16
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(Summary description)自1998年首个反义核酸类药物Fomivirsen上市至今，已有8款小核酸药物获批。2018年8月10日，由美国Alnylam制药公司开发的Onpattro（Patisiran）宣布获得美国FDA批准，用于由遗传性转甲状腺素蛋白淀粉样变性（hATTR）引起的周围神经疾病（多发性神经病变,polyneuropathy,FAP）成人患者，FAP为罕见的TTR基因突变引起的遗传疾病，TTR基因突变会造成

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下一代免疫&基因疗法突破口：小核酸药物

Categories:最新消息
Author:华讯知识产权
Origin:
Time of issue:2019-05-17 18:16
Views:

Information

自1998年首个反义核酸类药物Fomivirsen上市至今，已有8款小核酸药物获批。2018年8月10日，由美国Alnylam制药公司开发的Onpattro（Patisiran）宣布获得美国FDA批准，用于由遗传性转甲状腺素蛋白淀粉样变性（hATTR）引起的周围神经疾病（多发性神经病变, polyneuropathy, FAP）成人患者，FAP为罕见的TTR基因突变引起的遗传疾病，TTR基因突变会造成肝脏产生异常淀粉样蛋白沉积，进而损伤包括外周神经和心脏在内的身体器官和组织，诱发外周感觉神经病变、自主神经病变、和心肌病等疾病，严重影响生活质量且致死性高，此种疾病很难用传统药物控制，而RNA药物如Patisiran则能选择性降解TTR的mRNA避免毒性蛋白的合成。这是FDA批准的首款RNA干扰（siRNA）机制药物，也是FDA批准的首款用于治疗由hATTR引起的多发性神经病患者的疗法。

小核酸药物作用机制

大家都知道，生物体DNA上的基因片段信息主要通过信使RNA（mRNA）传递到蛋白质，而RNA干扰（RNA interference, RNAi）则是真核细胞特有的基因沉默机制以抵抗外来物质入侵、保护遗传信息的稳定性、调节生物体的各种机能。

RNA干扰（RNA interference, RNAi）是指由长链双RNA（double-stranded RNA, dsRNA）诱发的同源mRNA高效特异性降解的现象，dsRNA被剪切为20-25 bp的小干扰RNA（small interfering RNA, siRNA）后，装载到siRNA诱导干扰复合体（siRNA induced interference complex, RISC）中，RISC再与互补的目标基因mRNA以碱基配对的形式结合，诱导mRNA降解并最终静默特定基因表达。

基于RNAi建立的各种技术/药物应用通常被称为小核酸技术/药物，小核酸包括介导RNAi的短双链RNA片段（siRNA）、miRNA和反义核酸等，其中以siRNA药物目前最受关注。

传统的小分子药物及蛋白类药物靶点多为蛋白质，包括激酶、受体、抗原等，但不少疾病是由于基因突变导致对应的蛋白质出了问题，而RNAi的发现极大拓宽了人类药物的来源和开发方向，使药物靶点扩大至蛋白质的上游—RNA，使小核酸药物从转录后水平进行治疗，具有临床前研发周期短、候选靶点丰富、高特异性、高效性、长效性等优势。

小核酸药物的适应症涵盖范围广，包括肿瘤、罕见病（肌萎缩性脊髓侧索硬化、杜氏肌营养不良、脊髓性肌萎缩）、病毒性疾病、心血管疾病（凝血功能不足、血脂异常等）、炎症类疾病（哮喘、关节炎、结肠炎）等，但罕见病和肿瘤为其应用最广的领域。

我国小核酸制药的主要开拓者

在国内，苏州瑞博生物技术有限公司致力于开发RNA干扰技术的创新型药物。2017年12月，苏州瑞博与其战略合作伙伴美国Quark制药公司（Quark Pharmaceuticals, Inc.）开发的小核酸药物QPI-1007完成国内首例临床给药，小核酸药物QPI-1007拟用于治疗非动脉炎性前部缺血性视神经病变（NAION），同时具有治疗青光眼的潜力；2017年4月，苏州瑞博又宣布与核酸制药巨头Ionis签署合作协议，获得Ionis三个分别用于治疗代谢疾病和癌症的RNA靶向药物在中国的全部研发和商业化权利。

目前苏州瑞博已申请多项国内外发明专利，相关专利情形整理如下表。随着siRNA平台和技术的建立，公司已逐渐建立丰富的产品管线，包括针对乙型肝炎、高血脂症等适应症的siRNA疗法。

公开号	专利名称	申请日	法律状态
CN101820921B	一种抑制酪氨酸酶基因表达的siRNA及组合物和应用	2008-08-26	授权
CN101889087B	一种干扰靶基因表达的复合分子及其制备方法	2008-11-28	授权
EP2233573B1	A complex molecule interfering the expression of target genes and its preparing methods	2008-11-28	授权
CN101921745B	MATP基因的干扰靶位点序列和小干扰核酸及组合物和应用	2009-06-11	授权
CN101921744B	P基因的干扰靶位点序列和小干扰核酸及组合物和应用	2009-06-11	授权
CN102083983B	乙型肝炎病毒基因的小核酸干扰靶位点序列和小干扰核酸及组合物和应用	2009-08-03	授权
CN101868473B	一种寡核苷酸的制备方法	2009-09-22	授权
US8569476	Method for preparing oligonucleotide	2009-09-22	授权
EP2380896B1	Method for preparing oligonucleotide	2009-09-22	授权
JP5253578B2	オリゴヌクレオチドの合成方法	2009-09-22	授权
CN102028947B	FAM3B基因的抑制剂和组合物及抑制方法以及脂肪肝的疗法和抑制剂的制药用途	2009-09-29	授权
US8754058	Inhibitors of FAM3B gene, inhibitor compositions, inhibiting methods and applications of inhibitors in preparing pharmaceuticals	2010-11-26	授权
CN102140460B	小干扰核酸和药物组合物及其制药应用	2010-01-29	授权
CN102140461B	小干扰核酸和药物组合物及其制药应用	2010-01-29	授权
CN102140459B	一种小干扰核酸和药物组合物及其制药应用	2010-01-29	授权
CN102140458B	小干扰核酸和药物组合物及其制药应用	2010-01-29	授权
CN102337263B	抑制肠道病毒71型基因表达的siRNA及组合物和应用	2010-07-21	授权
CN102344477B	一种核苷酸和/或寡核苷酸及其制备方法	2010-07-27	授权
US9567364	Nucleotide and/or oligonucleotide and preparation process thereof	2011-07-20	授权
EP2599784B1	Nucleotide and/or oligonucleotide and preparation process thereof	2011-07-20	授权
JP5728086B2	ヌクレオチド及び/又はオリゴヌクレオチド並びにその合成方法	2011-07-20	授权
CN102727907B	一种小干扰RNA药物的给药系统和制剂	2011-04-13	授权
CN102827225B	一种核苷酸和/或寡核苷酸及其制备方法	2011-06-14	授权
CN103987846B	一种双链核酸及其在核糖核酸酶检测中的应用和试剂盒	2012-09-10	授权
US9540682	Double-stranded nucleic acid, use and kit thereof in ribonuclease detection	2012-09-10	授权
CN104024413B	小干扰RNA及其应用和抑制plk1基因表达的方法	2012-10-19	授权
CN106467915A	小干扰RNA及其应用和抑制plk1基因表达的方法	2012-10-19	实质审查
US9328348	Small interference RNAs, uses thereof and method for inhibiting the expression of plk1 gene	2012-10-19	授权
US9593335	Small interference RNAs, uses thereof and method for inhibiting the expression of PLK1 gene	2016-04-15	授权
CN105473164A	一种核酸和药物组合物及其应用	2014-08-26	实质审查
CN106467565A	一种脱氧核糖寡核苷酸及其制备方法	2016-03-02	公布后撤回
CN107849567A	一种siRNA、含有该siRNA的药物组合物和缀合物及它们的应用	2016-06-24	实质审查
CN108431224A	一种小干扰核酸和药物组合物及其用途	2016-08-31	实质审查
CN108220293A	一种小干扰核酸和药物组合物及其用途	2016-12-21	实质审查
CN108210510A	一种小干扰核酸药物组合物及其用途	2016-12-21	实质审查
CN108239643A	抑制人和动物中TIMP-1基因表达的siRNA、包含其的组合物及其应用	2016-12-23	实质审查
CN108239644A	一种小干扰核酸和药物组合物及其用途	2016-12-23	实质审查
CN108251420A	抑制人和动物中CTGF基因表达的siRNA、包含其的组合物及其应用	2016-12-28	实质审查
CN108251421A	抑制人和动物中COL1A1基因表达的siRNA、包含其的组合物及其应用	2016-12-28	实质审查
CN108265052A	一种小干扰核酸和药物组合物及其用途	2016-12-30	实质审查

小结

如小核酸药物这样的颠覆性技术，其发展历程注定跌宕起伏，但在一代代人的不懈努力下，小核酸技术也在不断取得突破性进展。小核酸药物技术的障碍不在于选择性，而是稳定性、免疫原性、大规模生产等传统药物较少遇见的困难，小核酸药物能否突破自身局限，成为继抗体药物之后一个新的生物制药产业方向，依然有待于药物递送、大规模合成等关键技术环节的突破。

参考资料：http://med.sina.com/article_detail_103_2_56987.html

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Electronic Arts pledges free use for five accessibility patents

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