CN104684923A - 手性核酸佐剂 - Google Patents
手性核酸佐剂 Download PDFInfo
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- CN104684923A CN104684923A CN201380047250.4A CN201380047250A CN104684923A CN 104684923 A CN104684923 A CN 104684923A CN 201380047250 A CN201380047250 A CN 201380047250A CN 104684923 A CN104684923 A CN 104684923A
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Abstract
本发明的目的在于提供稳定性优异的新型CpG寡核苷酸的立体异构体以及具有干扰素-α(IFNα)产生能力的CpG寡核苷酸。本发明涉及包含2~4个均由5'-X1X2CpGX3X4-3'(式(I))构成的序列以及14~32个核苷酸长的寡核苷酸。式(I)中,CpG表示含有磷酸骨架修饰的非甲基化CpG。X1X2是AA、AT、GA或GT中的任一个。X3X4是TT、AT、AC或CG中的任一个。寡核苷酸在CpG之外的位点含有至少一个S型立体异构体的磷酸骨架修饰。
Description
技术领域
本发明涉及一种CpG寡核苷酸及其用途。更具体地,本发明涉及CpG寡核苷酸的立体异构体以及通过使用所述立体异构体活化树突状细胞,从而控制由免疫细胞引起的疾病的治疗剂。
背景技术
日本公开公报特表第2002-513763号(专利文献1)、日本特表2002-514397号公报(专利文献2)、日本公开公报特表第2002-521489号(专利文献3)中公开了CpG寡核苷酸及其制造方法。
日本公开公报特表第2010-504750号公报(专利文献4)中,公开了在CpG基序的外侧含有亲油性取代核苷酸类似物的寡核苷酸使干扰素-α(IFN-α)产生的内容。
下述非专利文献1中,公开了作为三聚物的CpG寡核苷酸的S型立体异构体促进MAPK信号的内容。应予说明,本说明书通过引用将其全部内容并入说明书中。
在下述非专利文献1中,公开了序列PF-3512676(序列号128),所述序列的所有部分为硫代磷酸酯修饰的并为S型立体异构体。天然的寡核酸在生物体内容易分解。然而将寡核酸的磷酸酯键(P-O键)替换为硫代磷酸酯键(P-S键)的P-S修饰体具有在生物体内难以被分解的特点。
现有技术文献
专利文献
专利文献1:日本公开公报特表第2002-513763号
专利文献2:日本公开公报特表第2002-514397号
专利文献3:日本公开公报特表第2002-521489号
专利文献4:日本公开公报特表第2010-504750号
非专利文献
非专利文献1:Authur M.Krieg et al.OLIGONUCLROTIDES13:pp.491-499(2003)
非专利文献2:Clin Cancer Res.2008Jul 15;14(14):4532-42.
发明内容
发明所要解决的课题
例如,非专利文献2中公开的CpG寡核苷酸的全部序列为硫代磷酸酯修饰的。因此,在非专利文献2中公开的CpG寡核苷酸有时会有引发炎症、诱发毒性反应的问题。另一方面,如果除去非专利文献2中公开的CpG寡核苷酸的硫代磷酸酯骨架修饰,则存在核苷酸的稳定性降低的问题。
因此,本发明的目的在于提供稳定性优异的新型CpG寡核苷酸的立体异构体。
本发明的另一目的在于提供具有干扰素-α(IFNα)产生能力的CpG寡核苷酸的立体异构体。
本发明的另一目的在于提供使用CpG寡核苷酸活化树突状细胞来治疗特定疾病的治疗剂。
本发明的另一目的在于提供细胞毒性小的CpG寡核苷酸的立体异构体。
用于解决课题的手段
本发明基本上基于如下新发现:通过控制寡核酸的立体结构,提高寡核酸在生物体内的稳定性,由此即使不在全部的序列中导入P-S键,也能够提供在生物体内稳定的寡核苷酸。因为不是全部的序列都进行了P-S键修饰,所以本发明的寡核苷酸含有优异的生物体相容性。
至少一个上述目的通过以下发明得到了解决。即,本发明的第一个方面涉及包含2~4个均由5’-X1X2CpGX3X4-3’(式(I))构成的序列以及14~32个核苷酸长的寡核苷酸。
式(I)中,CpG表示不含有磷酸骨架修饰的非甲基化CpG。
X1X2是可以含有磷酸骨架修饰的AA、AT、GA或GT中的任一种。可以含有磷酸骨架修饰的AA、AT、GA或GT是指AA、AT、GA、GT中的任一个可以含有1或2个磷酸骨架修饰。以下同样。
X3X4是可以含有磷酸骨架修饰的TT、AT、AC、TA、TC或CG。
所述寡核苷酸可以在5’-X1X2CpGX3X4-3’之外的位点含有磷酸骨架修饰。即,所述寡核苷酸可以在由5’-X1X2CpGX3X4-3’构成的CpG基序之外的部分含有磷酸骨架修饰。然而,优选地,所述寡核苷酸在CpG基序之外的部分中含有至少1个磷酸骨架修饰。
所述寡核苷酸优选X1X2是可以含有磷酸骨架修饰的AT、GA或GT中的任一个,X3X4是可以含有磷酸骨架修饰的TT、AT、AC、TA、TC或CG。
所述寡核苷酸优选X1X2是不含有磷酸骨架修饰的AA、AT、GA或GT中的任一个,X3X4是不含有磷酸骨架修饰的TT、AT、AC、TC或CG。
5’-X1X2CpGX3X4-3’以外的含有至少一个磷酸骨架修饰位点的位点优选为S型的立体异构体。
本发明的寡核苷酸优选为包含以下序列中的任一个或由以下的任一个序列构成的寡核苷酸。
式1
式2
式3
式4
上述式中,*表示基于磷酸骨架修饰的立体异构体,上述各式中的至少一个*是S型的立体异构体。上述式中对应于5’-X1X2CpGX3X4-3’的位点的CG指不含有磷酸骨架修饰的非甲基化CpG。
本发明的寡核苷酸优选为X1X2是GA、X3X4是TT或AC的寡核苷酸。
本发明的寡核苷酸优选为5’-X1X2CpGX3X4-3’以外的位点的至少一个磷酸骨架修饰包含硫代磷酸酯的寡核苷酸。
以式(I)表示的5’-X1X2CpGX3X4-3’构成的序列部分为CpG基序。这样一来,本发明的寡核苷酸优选为在CpG基序5’末端侧或3’末端侧的位置含有由-(G)m-(m为2~10的整数)构成的序列部分的寡核苷酸。
本发明的寡核苷酸优选为在CpG基序3’末端侧的位置含有由-(G)m-(m为1~6的整数)构成的序列部分的寡核苷酸。
本发明的寡核苷酸优选为在CpG基序5’末端侧的位置含有TC、TA、TG、CC或由CC构成的序列部分的寡核苷酸。
本发明的寡核苷酸优选至少含有第一CpG基序和第二CpG基序,
第一CpG基序和第二CpG基序直接结合,或
在第一CpG基序和第二CpG基序之间含有由-(T)n-(n为1~3的整数)、TA或TC构成的序列部分。
本发明的寡核苷酸优选由
tSpcSpgacgttSptSptSpgacgttSptSptSpgacggg(序列号13),
tSpCSpgacgtSptSpgacgtSptSpgacggg(序列号18),以及
gSpgSpgacgacgtcgtcgSpgSpgSpgSpgSpg(序列号44)
中的任一个序列或从它们的任一序列中取代、插入、缺失或添加1、2或3个碱基而得的序列构成。这些寡核苷酸优选显示与序列号13、序列号18或序列号44同样的稳定性或活性。此处,序列中“cg”表示含有磷酸骨架修饰的非甲基化CpG。
本发明的寡核苷酸优选由
tSpcSpgacgttSptSptSpgacgttSptSptSpgacggg(序列号13),
tSpcSpgacgtSptSpgacgtSptSpgacggg(序列号18),或
gSpgSpgacgacgtcgtcgSpgSpgSpgSpgSpg(序列号44)构成。此处,序列中“cg”表示含有磷酸骨架修饰的非甲基化CpG。
本发明还提供包含上述任一种寡核苷酸的组合物。
本发明还提供包含上述任一种寡核苷酸的疫苗佐剂。
本发明还提供包含上述任一种寡核苷酸的、从树突状细胞中诱生干扰素-α(IFN-α)的诱生剂。
本发明还提供包含有效量的上述任一种寡核苷酸作为有效成分的治疗剂,其中,所述治疗剂可用于治疗传染性疾病、癌症、呼吸系统疾病、过敏性疾病、自身免疫性疾病或创伤。
发明效果
根据本发明,可以提供稳定性优异的新型CpG寡核苷酸。
根据本发明,可以提供含有免疫调节能力的CpG寡核苷酸。
根据本发明,能够提供以CpG低聚核苷酸为有效成分的包含免疫调节因子的治疗剂。
根据本发明,可以提供细胞毒性小的CpG寡核苷酸。
附图说明
图1涉及序列号26~28,是进行S型和R型寡核苷酸的血清中稳定性评价的用于替代图表的凝胶电泳照片。
图2涉及序列号43~45,是进行S型和R型的寡核苷酸的血清中稳定性评价的用于替代图表的凝胶电泳照片。
图3涉及序列号33~35,是进行S型和R型的寡核苷酸的血清中稳定性评价的用于替代图表的凝胶电泳照片。
具体实施方式
本发明的第一方面涉及包含2~4个均由5’-X1X2CpGX3X4-3’(式(I))构成的序列以及14~32个核苷酸长的寡核苷酸。
“寡核苷酸”或“寡聚”是指与多个核苷酸(即磷酸基团以及取代的有机碱基)结合的糖(例如核糖或脱氧核糖),其中所述取代的有机碱基为取代的嘧啶(例如胞嘧啶(C)、胸腺嘧啶(T)或尿嘧啶(U))或者取代的嘌呤(例如腺嘌呤(A)或鸟嘌呤(G))。正如本说明书中使用的,术语“寡核苷酸”是指寡核糖核苷酸(ORN)以及寡脱氧核糖核苷酸(ODN)二者。术语“寡核苷酸”还包括寡核苷(即不含磷酸的寡核苷酸)以及含有任意的其他有机碱基的聚合物。寡核苷酸可以由现有的核酸源(例如基因组或cDNA)得到,优选为合成的寡核苷酸(例如通过寡核苷酸合成而产生)。
式(I)中,CpG表示不含有磷酸骨架修饰的非甲基化CpG。C是2’-脱氧胞苷。G是2’-脱氧鸟苷。p是核苷间的磷酸二酯键。
式(I)中,X1X2是可以含有磷酸骨架修饰的AA、AT、GA或GT中的任一个。式(I)中,X3X4是可以含有磷酸骨架修饰的TT、AT、AC、TA、TC或CG。本发明的寡核苷酸可以在CpG之外的位点含有磷酸骨架修饰。所述所述寡核苷酸可以在由5’-X1X2CpGX3X4-3’构成的CpG基序之外的部分含有磷酸骨架修饰。另一方面,因为在所有核苷酸之间带硫代磷酸酯骨架修饰的磷酸骨架的寡核苷酸存在前述的问题,所以例如磷酸骨架中氧原子被硫原子取代的比例优选为20%~95%,也可以为30%~95%、20%~90%、40%~95%、40%~90%、40%~80%、50%~95%、50%~90%、50%~80%、60%~95%。
所述寡核苷酸的X1X2优选是可以含有磷酸骨架修饰的AT、GA或GT中的任一个,X3X4优选是可以含有磷酸骨架修饰的TT、AT、AC、TA、TC或CG。
所述寡核苷酸优选X1X2是不含有磷酸骨架修饰的AA、AT、GA或GT中的任一个,X3X4是不含有磷酸骨架修饰的TT、AT、AC、TC或CG。
在CpG基序之外的含有磷酸骨架修饰的位点是硫代磷酸酯的情况下,优选CpG基序之外的含有至少一个磷酸骨架修饰部分的位点可以是S型的立体异构体。在CpG基序之外的部分的至少一个磷酸骨架修饰被硫原子之外的原子或基团取代的情况下,所述位点在氧原子被硫原子取代时优选形成S型构象。
本发明的寡核苷酸优选包含以下序列中的任一个或优选为由以下的任一个序列构成的寡核苷酸。
式5
式6
式7
式8
上述式中,*表示基于磷酸骨架修饰的立体异构体。上述式中对应于5’-X1X2CpGX3X4-3’的部分的CG指不含有磷酸骨架修饰的非甲基化CpG。磷酸骨架修饰的实例为硫代磷酸酯骨架修饰、二硫代磷酸酯骨架修饰或氨基磷酸酯骨架修饰。在这些磷酸骨架修饰中,优选硫代磷酸酯骨架修饰。硫代磷酸酯骨架修饰是指将构成相邻核苷酸间的磷酸二酯键的磷原子上结合的2个非桥氧原子中的1个转换成硫原子。上述各式中的至少一个*是S型的立体异构体。此处,S型是指如上所述,当它们的代替氧原子导入的原子或基团为硫原子时,为S型的立体异构体。
本发明的寡核苷酸优选为由满足式(I)的序列或上述序列构成的寡核苷酸,其中X1X2为GA,X3X4为TT或AC。
本发明的寡核苷酸优选作为上述寡核苷酸中的任一种、并且在CpG基序之外的至少一个位点存在包含硫代磷酸酯的磷酸骨架修饰的寡核苷酸。即,如上述所说,优选在CpG之外的位点也含有硫代磷酸酯骨架修饰。在这种情况下,如上述所说,优选S型的立体异构体。不过,本发明中优选每个序列之间不存在硫代磷酸酯骨架修饰。
由式(I)所表示的5’-X1X2CpGX3X4-3’构成的序列部分为CpG基序。这样一来,本发明的寡核苷酸优选为在CpG基序5’末端侧或3’末端侧的位置含有由-(G)m-(m为2~10的整数)构成的序列部分的寡核苷酸。
本发明的寡核苷酸优选为在CpG基序5’末端侧的位置含有TC、TA、TG或由CC构成的序列部分的寡核苷酸。
本发明的寡核苷酸优选包括至少第一CpG基序和第二CpG基序,
第一CpG基序和第二CpG基序直接结合,或
在第一CpG基序和第二CpG基序之间含有由-(T)n-(n为1~3的整数)、TA或TC构成的序列部分。
本发明的寡核苷酸优选由
tSpcSpgacgttSptSptSpgacgttSptSptSpgacggg(将其称为序列号13),
tSpcSpgacgtSptSpgacgtSptSpgacggg(将其称为序列号18),以及
gSpgSpgacgacgtcgtcgSpgSpgSpgSpgSpg(将其称为序列号44)
中的任一个序列或从其中任一序列中取代、插入、缺失或添加1、2或3个碱基而得的序列构成。这些寡核苷酸优选展现与序列号13、序列号18或序列号44同样的稳定性或活性。此处,序列中“cg”表示含有磷酸骨架修饰的非甲基化CpG。“Sp”表示在相邻的核苷酸间导入S型的硫代磷酸酯骨架修饰。
本发明的寡核苷酸优选由
tSpcSpgacgttSptSptSpgacgttSptSptSpgacggg(将其称为序列号13),
tSpcSpgacgtSptSpgacgtSptSpgacggg(将其称为序列号18),或
gSpgSpgacgacgtcgtcgSpgSpgSpgSpgSpg(序列号44)构成。此处,序列中“cg”表示含有磷酸骨架修饰的非甲基化CpG。“Sp”表示在相邻的核苷酸间导入S型的硫代磷酸酯骨架修饰。
核苷酸的合成方法
核苷酸的合成方法是公知的。因此,本发明的核苷酸可以通过公知的方法制备。本发明的核苷酸可以采用例如日本专利第4580870号或国际公开第2010/064146号小册子中公开的方法。
与上述不同的其他核苷酸合成例是日本专利第4942646号公报中公开的方法、美国专利第5912332号说明书中公开的方法。后者将附着固体载体的连接子(linker)用于并行合成,或使用附着有磷酸盐的可控孔径玻璃(controlled pore glass)等通用的固体载体。
另外,核苷酸可以通过例如日本专利第4383534号公报中公开的方法制备。例如,可以使用β-氰基乙基氨基亚磷酸酯法(Beaucage SL以及Caruthers MH(1981)Tetrahedron Lett 22:1859)、以及核苷H-膦酸酯法(Garegg等(1986)Tetrahedron Lett27:4051-4;Froehler等(1986)Nucl Acid Res 14:5399-407;Garegg等(1986)Tetrahedron Lett 27:4055-8;Gaffney等(1988)Tetrahedron Lett 29:2619-22)从头合成。这些化学物质可以通过能够在市场上买到的各种自动核酸合成机合成。这些核酸被称为合成核酸。或者,可以在质粒中大规模地生成本发明的核酸(参见Sambrook T等,“Molecular Cloning:A LaboratoryManual”,Cold Spring Harbor Laboratory Press,New York,1989)。本发明的核酸可以分离成较小的片段,或可以作为整体施用。核酸可以使用公知技术(例如使用限制酶、外切酶或内切酶的技术),由现有的核酸序列(例如基因组序列或cDNA序列)制备。由此制备的核酸称为被分离的核酸。被分离的核酸一般是指由天然通常相关联的成分中分离出来的核酸。例如,被分离的核酸可以为从细胞中分离的核酸,从细胞核中分离的核酸,从线粒体中分离的核酸,或从染色质中分离的核酸。本发明的结合基序核酸包括合成的结合基序核酸以及被分离的结合基序核酸二者。
在体内使用时,如果必要的话,优选对分解具有一定抗性(例如被稳定化)的所述结合基序寡核苷酸。“被稳定化的核酸分子”是指对在体内的分解(例如外切酶或内切酶)具有一定抗性的核酸分子。核酸稳定化可以通过磷酸骨架修饰而实现。本发明优选被稳定化的核酸含有被修饰的骨架。所述核酸骨架的修饰增加了体内给药时所述结合基序寡核苷酸的活性。在一些情况下,含有硫代磷酸酯键的结合基序寡核苷酸含有最大的活性,保护核酸不被细胞内外切酶以及细胞内切酶分解。所述其他被修饰的核酸的实例包括被修饰的磷酸二酯核酸、磷酸二酯核酸和硫代磷酸酯核酸的组合物(即,嵌合体)、甲基膦酸酯、甲基硫代磷酸酯、二硫代磷酸酯、对乙氧基以及它们的组合物。
被修饰的骨架(例如,硫代磷酸酯)可以采用应用氨基磷酸酯化学或H-膦酸酯化学中的任一个的自动化技术合成。例如,芳基膦酸酯以及烷基膦酸酯可以如美国专利第4,469,863号所记载的那样生成;烷基磷酸三酯(如美国专利第5,023,243号以及欧州专利第092,574号所记载地那样,带电荷的氧部分被烷基化)可以使用市售试剂,通过自动化固相合成而产生。关于其他DNA骨架的修饰以及取代的方法已经被描述了(例如参见Uhlmann E andPeyman A(1990)Chem Rev 90:544;Goodchild J(1990)Bioconjugate Chem 1:165)。
通过合成而得到的寡核苷酸可以通过公知的方法进行纯化。例如,通过反相HPLC进行纯化,进行脱保护、脱盐和渗析。由此可以将本发明的寡核苷酸分离纯化。
本发明还提供包含上述任一种寡核苷酸的组合物。所述组合物是药物组合物。所述组合物包含有效量的上述任一种寡核苷酸,并且也可以包含合适的公知的载体。载体可以是水或醇这样的溶剂。另外,载体可以是任选的赋形剂、稀释剂、填充剂、盐、缓冲剂、稳定剂、增溶剂、脂质或本领域已知的用于药物组合物的其他物质。
本发明还提供包含上述任一种寡核苷酸的疫苗佐剂。如果必要的话,疫苗佐剂可以包含药学允许的载体。日本专利第4126252号公开了包含寡核苷酸的疫苗佐剂。本发明的包含寡核苷酸的疫苗佐剂也可以适当包含所述专利中公开的要素。
本发明还提供包含上述任一种寡核苷酸的、诱导树突状细胞产生干扰素-α(IFN-α)的诱生剂。本发明还提供包含有效量的上述任一种寡核苷酸作为有效成分的,治疗感染性疾病、癌症、呼吸系统疾病、过敏性疾病、自身免疫性疾病或创伤愈合的治疗剂。
本发明的感染性疾病治疗剂中的感染性疾病的实例是真菌感染、持续性真菌感染、细菌感染、念珠菌病、慢性皮肤粘膜念珠菌病(CMC)、曲霉病、隐球菌病、病毒感染、持续性病毒感染、人类免疫缺陷病毒(HIV)感染、B型肝炎病毒(HBV)感染、C型肝炎病毒感染、持续性细菌感染性疾病、分枝杆菌感染、结核分枝杆菌(M.tuberculosis)感染、牛分枝杆菌(M.bovis)感染以及麻风杆菌(M.leprae)感染。例如,日本专利第4688815号公报中公开了干扰素-α对包括C型肝炎病毒(HCV)感染的感染性疾病的治疗有效。例如,日本专利第4607452号公报中公开了干扰素-α对感染性疾病(例如,分枝杆菌症、疟疾、利什曼病、弓形虫病、血吸虫病或肝吸虫病)的治疗有效。本发明的感染性疾病治疗剂还通过产生干扰素-α而对感染性疾病的治疗有效。
本发明的癌症治疗剂中的癌症包括公知的癌症以及肿瘤。例如,在日本专利第4607452号公报以及日本公开公报特表第2011-503039号中公开了干扰素-α(IFN-α)对癌症或肿瘤的治疗有效。因此,本发明的癌症治疗剂还通过产生干扰素-α而对癌症或肿瘤的治疗有效。
本发明的呼吸系统疾病治疗剂中的呼吸系统疾病的实例是感冒、哮喘、过敏性鼻炎、支气管炎、肺炎、急性呼吸窘迫综合征(ARDS)、过敏性支气管肺曲霉病。例如,在日本公开公报特表第2004―505046号中公开了干扰素-α对这些呼吸系统疾病的治疗有效。因此,本发明的呼吸系统疾病治疗剂还通过产生干扰素-α而对呼吸系统疾病的治疗有效。
本发明的过敏性疾病治疗剂中的过敏性疾病的实例是全身性炎症反应综合征(SIRS)、过敏反应或者类过敏反应、过敏性血管炎、肝炎、肾炎、肾病、胰腺炎、鼻炎、关节炎、炎症性眼病(例如结膜炎等)、炎症性肠病(例如溃疡性结肠炎、克罗恩氏病、嗜酸细胞性胃肠炎等)、脑和心血管系统疾病(例如动脉硬化、血栓症、缺血/再灌注损伤、再狭窄、梗塞等)、皮肤病(例如皮炎(例如特应性皮炎、银屑病、接触性皮炎、湿疹、荨麻疹、瘙痒症等)等)、自身免疫性疾病(例如多发性硬化症、类风湿关节炎、全身性红斑狼疮、I型糖尿病、肾小球肾炎、斯耶格伦氏综合征等)、移植器官排斥反应。例如,在日本公开公报特表第2004―505046号中公开了干扰素-α对过敏性鼻炎的治疗有效。因此,本发明的过敏性疾病治疗剂也通过产生干扰素-α而对过敏性疾病的治疗有效。
本发明的自身免疫性疾病治疗剂中的自身免疫性疾病的实例为急性特发性血小板减少性紫癜、慢性特发性血小板减少性紫癜、西登哈姆氏舞蹈病、重症肌无力症、全身性红斑狼疮、狼疮性肾炎、风湿热、多腺性综合症、大疱性类天疱疮、糖尿病、过敏性紫癜、链球菌感染后肾炎(post-streptococcalnephritis)、结节性红斑、多发性大动脉炎(Takayasu's arteritis)、阿狄森氏病(Addison's disease)、类风湿关节炎、多发性硬化症、结节病、溃疡性结肠炎、多形性红斑、IgA肾病、结节性多动脉炎、強直性脊柱炎、肺出血-肾炎综合征(Goodpasture′s syndrome)、血栓闭塞性脉管炎(thromboangitisubiterans)、斯耶格伦氏综合征、原发性胆汁性肝硬化、桥本甲状腺炎、甲状腺毒症、硬皮病、慢性活动性肝炎、多肌炎/皮肌炎、多软骨炎、寻常性天疱疮(parnphigusvulgaris)、韦格纳肉芽肿病(Wegener’s granulomatosis)、膜性肾病、肌萎缩性侧索硬化、脊髄痨、巨细胞性动脉炎/多肌痛、恶性贫血、急进性肾小球肾炎、银屑病以及纤维性肺泡炎。例如,在日本公开公报特表第2007-528209号中公开了干扰素-α(IFN-α)对这些自身免疫性疾病的治疗有效。因此,本发明的自身免疫性疾病治疗剂还通过产生干扰素-α而对自身免疫性疾病的治疗有效。
本发明的创伤治疗剂中的创伤包括皮肤病、手术导致的创伤、增殖性瘢痕、瘢痕瘤。例如,在日本公开公报特表第2003-503313号公报中公开了干扰素-α对皮肤病的治疗有效。因此,本发明的创伤治疗剂还通过产生干扰素-α而对创伤的治疗有效。
干扰素-α(IFN-α)的诱生剂以及这些治疗剂可以通过例如日本专利第4383534号公报中公开的方法而制造。
本发明的寡核苷酸可用于诱导1型IFN(即,IFN-α以及IFN-β)。所述方法包括使能够表达1型IFN的细胞与有效量的本发明的结合基序寡核苷酸接触以诱导所述细胞表达1型IFN的过程。最近发现人的主要的IFN-α分泌细胞型是浆细胞样树突状细胞(pDC)。所述细胞型在PBMC中以非常低的频率(0.2~0.4%)存在,所述细胞型的特征为谱系阴性(即,CD3、CD14、CD19、CD56均未染色),CD11c阴性以及CD4、CD123(IL-3Rα)以及主要组织相容性复合体II类(MHC II类)表型阳性。测定1型IFN的方法是本领域技术人员公知的,作为这样的方法,例如可以举出酶联免疫吸附测定(ELISA)、生物测定法以及荧光细胞分析法(FACS)。这些类型的测定可以通过容易获得的市售的试剂以及试剂来进行。
另外,所述寡核苷酸作为用于诱导全身免疫应答及/或粘膜免疫应答的佐剂是有效的。本发明的结合基序寡核苷酸可以被送达暴露于抗原的受试体以诱导对抗原的免疫应答的增强。因此,例如,结合基序寡核苷酸作为疫苗佐剂是有用的。佐剂作为辅助剂起作用的主剂的实例为各种疫苗。佐剂能够提高例如抗原被引入免疫细胞的效率。佐剂优选能够辅助或增强或改善主剂的有效成分原有的作用。作为对象的疫苗的实例为病毒疫苗以及用于B型肝炎、A型肝炎、流行性乙型脑炎、小儿肺炎球菌肺炎、白喉、百日咳、破伤风、麻疹、风疹、腮腺炎、水痘、结核(BCG疫苗)的疫苗。病毒疫苗的实例是流感疫苗、脊髓灰质炎疫苗、人乳头瘤病毒疫苗、轮状病毒疫苗、Hib疫苗(b型流感嗜血杆菌疫苗)、脊髓灰质炎疫苗以及艾滋病疫苗。本发明的寡核苷酸作为佐剂以非常少的量发挥作用。因此,本发明的寡核苷酸与常规佐剂相比细胞毒性低,副作用的可能性极低。对施用于众多对象的疫苗来说极为有益。
所述寡核苷酸可与非核酸佐剂组合给药。非核酸佐剂是指除本说明书中记载的寡核苷酸以外的,能够刺激体液免疫应答及/或细胞免疫应答的任意分子或化合物。非核酸佐剂的实例是产生贮存(depot)效应的佐剂、免疫刺激佐剂以及产生贮存效应并且刺激免疫系统的佐剂。在本说明书中使用的非核酸粘膜佐剂,是除寡核苷酸以外的,在与抗原一同施用于粘膜表面的情况下能够诱发受试体的粘膜免疫应答的佐剂。
本发明的寡核苷酸能够在药学允许的载体中配制成药物组合物。所述寡核苷酸可直接给予受试体或与核酸递送复合物组合给予受试体。核酸递送复合物是指与靶向方式(例如产生较高亲和性的结合于靶细胞(例如B细胞表面)的分子及/或增加通过靶细胞的细胞摄取的分子)缔合(例如,离子键或者共价键,或所述包封的方式)的核酸分子。核酸递送复合物的实例是与甾醇(例如胆固醇)缔合的核酸、与脂质(例如阳离子脂质、病毒体或脂质体)缔合的核酸,或与靶细胞特异性结合因子(例如通过靶细胞特异性受体识别的配体)缔合的核酸。优选的复合物能够在体内足够稳定,以防止被所述靶细胞内化前发生显著的解偶联。但是,所述复合物在所述细胞中于合适的条件下能够裂解从而以功能性的形式释放出所述核酸。
所述寡核苷酸及/或抗原及/或其他治疗剂可以单独给药(例如在生理盐水或者缓冲液中),或者可以使用本领域公知的任意的递送载体进行给药。
本说明书中记载的用于粘膜递送或者局部递送的化合物的受试体剂量,典型的范围约为0.1μg/剂量(μg/dose)~10mg/剂量,这取决于其是否是每日、每周或每月给药,还是能够在此期间的其他任意时间内进行。更典型地,粘膜给药剂量或局部给药剂量的范围约为10μg/剂量~5mg/剂量。最典型地,范围约为100μg/剂量~1mg/剂量,经过几日或几周的间隔进行2~4倍的给药。更典型地,免疫刺激剂的剂量的范围约为1μg/剂量~10mg/剂量,最典型地,范围约为10μg/剂量~1mg/剂量,每日或每周给药。为了诱导抗原特异性免疫应答,本说明书中记载的用于肠胃外递送的化合物的受试体剂量(所述化合物与抗原一同递送,而没有与其他治疗剂一同递送),典型地为用于疫苗佐剂或免疫刺激剂的有效的粘膜给药剂量的5倍~10000倍,更典型地为10倍~1000倍以上,最典型地为20倍~100倍以上。在所述寡核苷酸与其他治疗剂组合给药或者通过特殊的递送载体给药的情况下,本说明书中记载的用于诱导先天免疫应答或用于增加ADCC或用于诱导抗原特异性免疫应答的用于肠胃外递送的化合物的剂量,典型的范围约为0.1μg/剂量~10mg/剂量,这取决于其是否每日、每周或每月给药,还是能够在此期间的其他任意时间内进行。更典型地,用于这些目的的肠胃外剂量的范围约为10μg/剂量~5mg/剂量,最典型地,约为100μg/剂量~1mg/剂量,经过几日或几周的间隔进行2~4倍的给药。但是,在一些实施例中,用于这些目的的肠胃外剂量可以在上述典型剂量的5倍~10000倍的范围内使用。
如本说明书所使用的,“有效(的)量”是指为了实现所希望的生物效应所必需的或足够的量。例如,治疗感染性疾病的免疫核酸有效量是治疗所述感染性疾病所必需的量。结合本说明书中提供的启示(teaching),通过选择各种活性化合物以及加权因子(例如効力、相对生物利用度、患者的体重、不良副作用的严重程度以及优选的给药方式),可以规划有效的预防方案或者有效的治疗方案;所述方案不造成实质性的毒性,但对治疗特定的受试体完全有效。用于任意特定应用的有效量可以根据各种因素改变,所述因素包括如被治疗的疾病或者病症、所给予的特定的寡核苷酸、抗原、受试体的大小或其疾病或者病症的严重程度。本领域技术人员无需过多试验,凭经验即可确定特定的寡核苷酸及/或抗原及/或其他治疗剂的有效量。
对于本说明书中记载的任意化合物,其治疗上有效的量可以首先通过动物模型来确定。治疗上有效的剂量还可以由关于在人体试验(人类临床试验已经开始)的CpG寡核苷酸的数据以及已知表现出类似药理学活性的化合物(例如其他粘膜佐剂(例如LT以及疫苗接种用的其他抗原))的粘膜给药或者局部给药数据来确定。肠胃外给药需要更高剂量。应用的剂量可基于所给药的化合物的相对生物利用度以及効力进行调整。基于上述方法以及其他方法调整其剂量以达到最大効力是本领域公知的,完全在本领域技术人员的能力范围内。
本发明的制剂溶于在药学可接受的溶液中给药,所述溶液通常可包括药学可接受浓度的盐、缓冲剂、保存剂、相容的载体、佐剂以及根据需要的其他治疗成分。
对于在治疗中使用,可通过将所述核酸递送到所希望的表面(例如粘膜表面、全身表面)的任意方式,将有效量的所述寡核苷酸给予受试体。本发明的药物组合物的给药可通过本领域技术人员公知的任意手段来实现。优选的给药途径包括但不限于,口服途径、肠胃外途径、肌内途径、鼻内途径、气管内途径、吸入途径、眼内途径、舌下途径、阴道内途径以及直肠途径。
对于口服给药,所述化合物(即寡核苷酸、抗原以及其他治疗剂)可通过将所述活性化合物与本领域公知知的药学可接受的载体组合而容易地配制。这样的载体可将本发明的化合物配制成用于被目标受试体口服摄取的片剂、丸剂、糖锭剂、胶囊剂、液剂、凝胶剂、糖浆剂、浆液(slurry)剂、混悬剂以及类似的制剂。必要时,用于口服给药的药学制剂可以作为固体赋形剂获得,所述固体赋形剂可以通过制剂在所希望的情况下添加合适的助剂,随后研磨生成的混合物,加工所述颗粒混合物以得到片剂核或糖锭剂核而获得。合适的赋形剂特别是填充剂(例如糖(乳糖、蔗糖、甘露糖醇或者山梨糖醇)、纤维素制剂制剂(例如玉米淀粉、小麦淀粉、水稻淀粉、马铃薯淀粉、明胶、黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠)及/或聚乙烯基吡咯烷酮(PVP))。必要时,可以添加崩解剂(例如交联聚乙烯基吡咯烷酮、琼脂或褐藻酸或者其盐(例如褐藻酸钠))。必要时,所述口服制剂还可以在用于中和内部的酸性状态的生理盐水或者缓冲液中配制给药或不经任何载体进行给药。
糖锭剂核含备合适的包衣。为了所述目的,可以使用浓缩的糖溶液,必要时所述浓缩的糖溶液可包含阿拉伯胶、滑石、聚乙烯基吡咯烷酮、卡波姆(Carbopol)凝胶、聚乙二醇及/或二氧化钛、漆溶液以及合适的有机溶剂或者溶剂混合物。为了鉴定或表征不同的活性化合物剂量的组合,可将染料或色素添加到片剂或糖锭剂包衣中。
可口服给药的药学制剂的实例为由明胶制作的推入配合式(push-fit)胶囊,以及由明胶和增塑剂(例如甘油或山梨糖醇)制作的软密封胶囊。所述推入式(push-fit)胶囊可包含必要时与填充剂(例如乳糖)、粘合剂(例如淀粉)及/或润滑剂(例如滑石或硬脂酸镁)以及稳定剂混合的活性成分。在所述软胶囊中,可将活性化合物溶解或混悬在合适的液体(例如脂肪油、液体石蜡或液体聚乙二醇)中。此外,可添加稳定剂。也可以使用为了口服给药配制的微球体。这样的微球体在本领域中已被熟知。用于口服给药的全部制剂可以通过适当的剂量给药。
对于口腔含化给药,所述组合物可以采用通常规方式配制的、片剂或糖锭剂的形式。
对于吸入给药,本发明的化合物可以如现有技术一样地递送,使用合适的推进剂(例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其他合适的气体)从加压包或喷雾器中喷出气溶胶喷雾给药。在使用加压气溶胶的情况下,其给药单位可通过提供阀门来递送所计量的量而确定。在用于吸入器或注气器时,可以配制使用的例如明胶的胶囊以及药筒,其中包含所述化合物与合适的粉末基剂(例如乳糖或淀粉)的粉末混合物。
在希望所述化合物全身递送的情况下可配制成通过注射(例如推注(bolus infusion)或连续输注)的肠胃外给药形式。用于注射的制剂可以与所添加的保存剂一同以单位剂量形式存放(例如在安瓿或多剂量容器中)。所述组合物可采用如油状或者水性载体中的混悬物、溶液或乳液这样的形式,可包含制剂(例如混悬剂、稳定剂及/或分散剂)。
用于肠胃外给药的药学制剂的实例包括水溶性的所述活性化合物的水溶液。此外,所述活性化合物的混悬物可作为合适的油状注射混悬物配制。所述合适的亲油性溶剂或亲油性载体,包括脂肪油(例如芝麻油)或合成脂肪酸酯(例如油酸乙酯或者甘油三酯)或脂质体。水性注射混悬物可包含增加所述混悬物的粘度的物质(例如羧甲基纤维素钠、山梨糖醇或葡聚糖)。为了能够配制高度浓缩的溶液,必要时,所述混悬物可包含增加合适的稳定剂或所述它们的化合物的溶解度的药剂。
或者,所述活性化合物可以是在使用前可采用合适的载体(例如灭菌无热原水)配制的粉末形态。
所述化合物还可以以直肠组合物或阴道内组合物(例如,包含常规的栓剂基剂(例如,可可脂或其他甘油酯))的栓剂或保留灌肠剂)的形式配制。
除了上述制剂,所述化合物还可以配制成贮存(depot)制剂。这样的长效制剂可以使用合适的聚合物或者疏水性材料(例如可接受的油中的乳液),或使用离子交换树脂,或溶解性差的衍生物(例如,水溶性差的盐),进行配制。
另外,所述药物组合物可包含合适的固相或者凝胶相的载体或者赋形剂。这样的载体或赋形剂的实例,包括但不限于,碳酸钙、磷酸钙、各种糖、淀粉、纤维素衍生物、明胶以及聚合物(例如聚乙二醇)。
合适的液体药物制剂的形式或固体药物制剂的形式为,例如被微胶囊化、螯合的、被涂覆在黄金微粒上、被包含在脂质体中、被包含在待喷射的气雾剂中、被包含在用于移植到皮肤中的小丸中、或被干燥在对皮肤进行搔挠的尖锐物体上的、用于吸入的水溶液或者生理盐水溶液。所述药物组合物还包含可以长期释放活性化合物的,颗粒剂、散剂、片剂、包衣片剂、(微)胶囊剂、栓剂、糖浆剂、乳剂、混悬剂、霜剂、滴剂或制剂,如上所述,所述制剂包括常用的赋形剂以及添加剂及/或佐剂(例如崩解剂、粘合剂、包衣剂、甜味剂、润滑剂、调味剂、甜味剂或增溶剂)。所述药物组合物适用于各种药物递送系统。对于用于药物递送方法的简要综述,参见Langer(1990)Science 249:1527-33(将其通过引用并入本文)。
所述寡核苷酸以及其他治疗剂及/或抗原,必要时其本身可(直接)给药或以药学可接受的盐的形式给药。在药物中使用的情况下,其盐应为药学可接受的,药学不可接受的盐可简便地用于调制其药学可接受的盐。作为这样的盐,包括但不限于以下的酸配制的盐,即,盐酸、氢溴酸、硫酸、硝酸、磷酸、马来酸、乙酸、水杨酸、对甲苯磺酸、酒石酸、柠檬酸、甲磺酸、甲酸、丙二酸、琥珀酸、萘-2-磺酸以及苯磺酸。另外,这样的盐可配制为碱金属盐或碱土金属盐(例如羧酸的钠盐、钾盐或者钙盐)。
合适的缓冲化剂包括乙酸及其盐(1~2%w/v);柠檬酸及其盐(1~3%w/v);硼酸及其盐(0.5~2.5%w/v);以及磷酸及其盐(0.8~2%w/v)。合适的保存剂包括苯扎氯铵(0.003~0.03%w/v);氯丁醇(0.3~0.9%w/v);对羟基苯甲酸酯(0.01~0.25%w/v),以及硫柳汞(0.004~0.02%w/v)。
必要时,本发明的药物组合物可将有效量的寡核苷酸、必要时使用的抗原及/或其他药剂包含在药学可接受的载体中。术语“药学可接受的载体”是指一种或多种相容的填充剂、稀释剂或者包封剂,其为固体或者液体并适于施用给人或其他脊椎动物。术语“载体”是指被添加以促进活性成分的应用的天然或者合成的有机成分或者无机成分。所述药物组合物的成分还可以以不相互作用的方式,与本发明的化合物彼此混合。
对于受试体的治疗,根据所述化合物的活性、给药方式、免疫目的(即,预防免疫或治疗免疫)、所述疾病的性质以及严重程度、患者的年龄以及体重,本发明的药物组合物不同的剂量是必需的。规定剂量的给药可以以对应剂量单位的量一次给药,或以少于剂量单位的量多次给药。
其他递送体系的实例包括定时释放(time-release)体系、延迟释放(delayed release)体系或缓释(sustained release)体系。这样的体系可避免所述化合物的反复给药,能够增加受试体以及医师的便利。可利用多种类型的释放递送体系,这对本领域技术人员来说是公知的。这些体系的实例包括基于聚合物的体系(例如,聚(丙交酯-乙交酯)、共聚草酸酯、聚己内酯、聚酯酰胺、聚原酸酯、聚羟基丁酸以及聚酸酐)。例如在美国专利第5,075,109号中记载了包含药物的上述聚合物的微型胶囊。所述递送体系,还可以包括非聚合物体系。所述非聚合物体系的实例包括脂质(甾醇(例如胆固醇、胆固醇酯),以及脂肪酸或者天然脂肪(例如甘油单酯、甘油二酯以及甘油三酯));水凝胶释放体系;硅橡胶(silastic)体系;基于肽的体系;蜡包衣;使用常规粘合剂以及赋形剂的压缩片剂;部分融合的植入物等。所述体系的特定实例,包括但不限于(a)本发明的药剂以存在于基质中的形式包含的侵蚀体系(美国专利第4,452,775号,美国专利第4,675,189号以及美国专利第5,736,152号中记载的体系);以及(b)活性成分以被控制的速度从聚合物渗透的扩散体系(记载于美国专利第3,854,480号,美国专利第5,133,974号以及美国专利第5,407,686号)。另外,可使用基于泵的硬件递送体系,其中的一些可适于植入。
本发明通过以下的实施例进一步说明。以下的实施例在任何情况下都不应解释为进一步限定。本说明书全文中参考文献的全部内容通过引用被并入本文。
实施例1
手性CpG寡核酸的合成
CpG寡核酸(mix体)
使用氨基亚磷酸酯法进行合成并通过HPLC纯化的寡核酸(Mix体)从Gene Design公司购入。
立体控制的CpG寡核酸的合成
通过重复以下(i)~(iv)的步骤进行核酸链的延伸。
(i)3%DCA(二氯乙酸)/CH2Cl2(15秒);
(ii)缩合反应((0.1M单体的MeCN溶液(参见下述内容)和1M PhIMT(1-苯基咪唑三氟甲磺酸酯)的MeCN溶液的1:1混合溶液,5分钟));
(iii)封端反应(0.5M CF3COIm的THF溶液和1M DMAN(1,8-双二甲基氨基萘)的THF溶液的1:1混合液,30秒);以及
(iv)硫化反应(0.1M DDTT的MeCN溶液,90秒)或者氧化反应(0.02M I2的H2O-嘧啶(Pyridine)-THF溶液,15秒)。
链延伸后,将固相载体回收到1.5mL微管中,用浓氨水(1.2mL,55℃,48小时)处理。通过过滤去除固相载体,将滤液减压干燥后,溶于水(1.0mL),通过反相HPLC进行分离纯化得到寡聚物。
0.1M单体的MeCN溶液调制方法(在Rp-Th的情况下)
将胸苷酸H-膦酸酯(phosphonate)单酯(25μmol)用脱水吡啶、脱水甲苯共沸干燥后,溶于MeCN-CMP(N-氰基甲基吡咯烷)混合液(9:1,v/v;250μL)。在溶液中加入Ph3PCl2(62.5μmol),搅拌10分钟,随后加入AA-L(30μmol;Sp体的情况下AA-D),再搅拌10分钟,由此调制单体溶液。
上述说明中,DDTT、AA-L以及AA-D分别是以下化合物的简称。得到的寡核酸如表1所示。
[化学式1]
[表1-1]
表1实施例1中得到的寡核酸
[表1-2]
表中,*表示随机导入了S型以及R型的硫代磷酸酯骨架修饰。表中,s表示导入S型的硫代磷酸酯骨架修饰。表中,r表示导入R型的硫代磷酸酯骨架修饰。
实施例2
猴外周血单核细胞(PBMC)中的IFN-α的产生诱导
将乙型肝炎病毒阴性的食蟹猕猴血液(购自株式会社新日本科学)用Hank平衡盐溶液(Hanks’Balanced Salt Solution)稀释3倍,层叠在Ficoll-Paque PLUS分离液上后,进行离心分离(2600rpm,30min),采集包含猴外周血单核细胞(PBMC)的部分。将PBMC用RPMI培养基(+1%青霉素-链霉素)清洗后,在RPMI培养基(+10%FBS,1%青霉素-链霉素)中配制成细胞浓度为3×106cells/mL。然后,接种在96孔U底板中,与各种寡核酸(含有以1:3.2混合的寡DNA与DOTAP的混合物)一同在5%CO2培养器中培养17~24小时。培养结束后,通过离心分离(500rpm,5min),回收培养上清液。使用ELISA试剂盒(ELISAKit)(PBL公司),对培养上清液中的IFN-α的浓度进行测定。
测定结果如表2所示。表2涉及序列号1~48,表现出对猴外周血单核细胞(PBMC)中的IFN-α的产生的诱导作用。
[表2]猴末梢血单核细胞中的IFN-α产生的诱导作用
实施例3
猴血清中(寡核酸)的稳定性评价
样品制备
对乙型肝炎病毒阴性的食蟹猕猴血液(购自株式会社新日本科学)进行离心分离(3000rpm,15min),得到血清。使寡核酸(13.4ng/μL)于37℃的水浴内在50%猴血清中反应,进行取样。使回收的样品在0.3mg/mL蛋白酶(Proteinase)K的存在下于42℃反应1.5小时后,添加与样品等体积的苯酚/氯仿溶液,离心分离(10000rpm,5min)后,收集水层以作为供SDS-PAGE分析的样品。
SDS-PAGE的实施
将通过上述方法得到的样品(100.5ng)添加到20%改性聚丙烯酰胺凝胶中,以20mA进行120分钟的电泳后,用稀释10000倍的SYBR-Gold溶液染色40分钟。用UV透照器将寡核酸以荧光带的形式可视化,通过图像分析仪(IMAGE STATION:Koda公司)对荧光强度进行测定。
其结果示于图1~图3及表3。图1涉及序列号27~28,是进行S型和R型的寡核苷酸的血清中稳定性评价的用于代替图表的凝胶电泳照片。图2涉及序列号43~45,是进行S型和R型的寡核苷酸的血清中稳定性评价的用于代替图表的凝胶电泳照片。图3涉及序列号33~35,是进行S型和R型的寡核苷酸的血清中稳定性评价的用于代替图表的凝胶电泳照片。
[表3]血清中稳定性评价
实施例4
小鼠中的抗原特异性抗体的产生诱导试验
受试物质的给药
将作为免疫抗原的OVA(和光纯药)以及寡核酸,分别使用生理盐水配制成0.2mg/mL,作为受试物质的给药液。
模型的制备
使用8周龄的BALB/cAnCrlCrlj小鼠,通过全身麻醉装置,用异氟烷(2.0%~4.0%,Forane,日本雅培公司)维持麻醉状态,对动物的背部进行剪毛,使用一次性注射筒以及注射针,将被检物质给药液以50μL/body的剂量对背部皮内进行给药。第一次给药2周后进行再次给药,一周后实施安乐死,采集脾脏以及全部血液。
抗体效价测定
将从给药日的5日前以及第16日后采集的血液中分离的血浆用作样品。将固相化溶液以0.1mL/well添加到ELISA板中,将板密封后,冷藏静置一夜。除去溶液,添加0.3mL/well清洗液,将清洗液除去。将同样的操作重复2次,共计清洗3次。添加0.2mL/well封闭溶液,将板密封后,在室温下静置1~4小时。将溶液除去,通过与上述同样的方法清洗3次。
将待测样品(血浆)用稀释液稀释至100倍,之后以每次稀释2倍的稀释率稀释7个梯度(即可得稀释100~12800倍的样品),并按0.1mL/well加入到ELISA板的孔中。作为空白,将稀释液加入到另一个孔中,将板密封后,在设定为37℃的平板培养器中温育1小时。将溶液除去,通过与上述同样的方法清洗3次。按0.1mL/well添加检测抗体溶液,将板密封后,在设定为37℃的平板培养器中温育1小时后,将溶液除去,以上述同样的方法清洗4次。
按0.1mL/well添加底物显色液,于室温使其反应30分钟后,按0.1mL/well添加终止液,使反应停止。使用多板用吸光度测定装置(主波长450nm,副波长620nm),对各孔的吸光度进行测定。
其结果示于表4。表4表示序列号27以及28的寡核苷酸的抗OVA-IgG抗体效价测定。由表4可知,与R型相比,S型的寡核苷酸可诱导更优异的抗体效价。
[表4]手性CpG寡核酸对抗OVA-IgG抗体效价的作用
脾脏重量的测定
将采集的脾脏用冷的生理盐水清洗后,使用电子天平(HR-200,A&D公司)对脾脏重量进行测定。
其结果示于表5。表5表示序列号27以及28的寡核苷酸对脾脏重量的影响。由表5可知,施用R型的寡核苷酸使得脾脏重量增加。这表示R型的寡核苷酸含有毒性。另一方面,施用S型的寡核苷酸没有使脾脏重量增加。这表示S型的寡核苷酸不含有毒性或毒性低。
[表5]手性CpG寡核酸对脾脏重量的作用
实施例5
使用与实施例1同样的方法合成立体控制的CpG寡核酸。通过合成得到的寡核酸的碱基序列示于下表6。表中的符号与实施例1中的一样。应予说明,为了参考,将已知的核酸的序列表示为序列号119。
[表6-1]
表6实施例5中得到的寡核酸
[表6-2]
实施例6
使用与实施例2同样的方法,使用与序列号128所表示的已知的核酸的相对值,评价通过实施例5合成的寡核酸对猴外周血单核细胞(PBMC)中的IFN-α产生的诱导。其结果示于表7。
[表7-1]
表7猴外周血单核细胞(PBMC)中的IFN-α产生的诱导作用
[表7-2]
对于序列119(常规的聚核苷酸),以与实施例2同样的方式测定IFN-α的浓度值,如表8所示。
[表8]
表8IFN-α的浓度值测量值
产业上的可利用性
本发明可以用于制药产业。
Claims (17)
1.一种寡核苷酸,是包含2~4个均由5’-X1X2CpGX3X4-3’构成的序列以及14~32核苷酸长的寡核苷酸,其特征在于,
所述CpG是不含有磷酸骨架修饰的非甲基化CpG,
所述X1X2是可以含有磷酸骨架修饰的AA、AT、GA或GT中的任一个,
所述X3X4是可以含有磷酸骨架修饰的TT、AT、AC、TA、TC或CG,
所述寡核苷酸在所述5’-X1X2CpGX3X4-3’之外的位点含有至少一个磷酸骨架修饰。
2.根据权利要求1所述的寡核苷酸,其中,
所述X1X2是可以含有磷酸骨架修饰的AT、GA或GT中的任一个,
所述X3X4是可以含有磷酸骨架修饰的TT、AT、AC、TA、TC或CG。
3.根据权利要求1所述的寡核苷酸,其中,
所述X1X2是不含有磷酸骨架修饰的AA、AT、GA或GT中的任一个,
所述X3X4是不含有磷酸骨架修饰的TT、AT、AC、TC或CG。
4.根据权利要求1所述的寡核苷酸,其中,
所述5’-X1X2CpGX3X4-3’之外的位点中的含有至少一个磷酸骨架修饰的位点为S型的立体异构体。
5.根据权利要求1所述的寡核苷酸,其中,
包含以下序列中的任一个:
上述式中*表示基于磷酸骨架修饰的立体异构体,上述各式中的至少一个*是S型的立体异构体,
上述式中对应于5’-X1X2CpGX3X4-3’的位点中的CG指不含有磷酸骨架修饰的非甲基化CpG。
6.根据权利要求1所述的寡核苷酸,其中,
所述X1X2是GA,
所述X3X4是TT或AC。
7.根据权利要求1所述的寡核苷酸,其中,
所述5’-X1X2CpGX3X4-3’之外的位点中的至少一个磷酸骨架修饰包含硫代磷酸酯。
8.根据权利要求1所述的寡核苷酸,其中,
以所述由5’-X1X2CpGX3X4-3’构成的序列部分为CpG基序时,在所述CpG基序5’末端侧或3’末端侧的位置含有由-(G)m-(m为2~10的整数)构成的序列部分。
9.根据权利要求1所述的寡核苷酸,其中,
以所述由5’-X1X2CpGX3X4-3’构成的序列部分为CpG基序时,在所述CpG基序3’末端侧的位置含有由-(G)m-(m为1~6的整数)构成的序列部分。
10.根据权利要求1所述的寡核苷酸,其中,
以所述由5’-X1X2CpGX3X4-3’构成的序列部分为CpG基序时,在所述CpG基序5’末端侧的位置含有TC、TA、TG、CC或由CC构成的序列部分。
11.根据权利要求1所述的寡核苷酸,其中,
以所述由5’-X1X2CpGX3X4-3’构成的序列部分为CpG基序时,至少含有第一CpG基序和第二CpG基序,
第一CpG基序和第二CpG基序直接结合,或
在第一CpG基序和第二CpG基序之间含有由-(T)n-(n为1~3的整数)、TA或TC构成的序列部分。
12.根据权利要求1所述的寡核苷酸,其中,由下述的任一序列或从任一序列中取代、插入、缺失或添加1、2或3个碱基而得的序列构成,
序列号13:
t Sp c Sp g a c g t t Sp t Sp t Sp g a c g t t Sp t Sp t Sp g ac g g g,
序列号18:
t Sp c Sp g a c g t Sp t Sp g a c g t Sp t Sp g a c g g g,以及
序列号44:
g Sp g Sp g a c g a c g t c g t c g Sp g Sp g Sp g Sp g Sp g,
序列中“cg”表示含有磷酸骨架修饰的非甲基化CpG,
“Sp”表示在相邻的核苷酸间导入S型的硫代磷酸酯骨架修饰。
13.根据权利要求1所述的寡核苷酸,其中,由下述序列构成:
序列号13:
t Sp c Sp g a c g t t Sp t Sp t Sp g a c g t t Sp t Sp t Sp g ac g g g,
序列号18:
t Sp c Sp g a c g t Sp t Sp g a c g t Sp t Sp g a c g g g,或
序列号44:
g Sp g Sp g a c g a c g t c g t c g Sp g Sp g Sp g Sp g Sp g,
序列中“cg”表示含有磷酸骨架修饰的非甲基化CpG,
“Sp”表示在相邻的核苷酸间导入S型的硫代磷酸酯骨架修饰。
14.一种包含根据权利要求1所述的寡核苷酸的组合物。
15.一种包含根据权利要求1所述的寡核苷酸的疫苗佐剂。
16.一种包含根据权利要求1所述的寡核苷酸,从树突状细胞中诱生干扰素-α(IFN-α)的诱生剂。
17.一种包含有效量的根据权利要求1所述的作为有效成分的寡核苷酸的治疗剂,其中所述治疗剂可用于治疗感染性疾病、癌症、呼吸系统疾病、过敏性疾病、自身免疫性疾病或创伤。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106256905A (zh) * | 2015-11-24 | 2016-12-28 | 华中农业大学 | 一种对草鱼有免疫增强活性的CpG ODN序列及其应用 |
Families Citing this family (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BRPI0923225A2 (pt) | 2008-12-02 | 2016-10-04 | Chiralgen Ltd | metodo para sintese de acidos nucleicos modificados no atomo de fosforo |
CA2767253A1 (en) | 2009-07-06 | 2011-01-13 | Ontorii, Inc. | Novel nucleic acid prodrugs and methods of use thereof |
WO2012039448A1 (ja) | 2010-09-24 | 2012-03-29 | 株式会社キラルジェン | 不斉補助基 |
EP2734208B1 (en) | 2011-07-19 | 2017-03-01 | Wave Life Sciences Ltd. | Methods for the synthesis of functionalized nucleic acids |
CA2879066C (en) * | 2012-07-13 | 2019-08-13 | Shin Nippon Biomedical Laboratories, Ltd. | Chiral nucleic acid adjuvant |
WO2014010250A1 (en) | 2012-07-13 | 2014-01-16 | Chiralgen, Ltd. | Asymmetric auxiliary group |
KR20220139425A (ko) | 2012-07-13 | 2022-10-14 | 웨이브 라이프 사이언시스 리미티드 | 키랄 제어 |
US10894963B2 (en) | 2013-07-25 | 2021-01-19 | Exicure, Inc. | Spherical nucleic acid-based constructs as immunostimulatory agents for prophylactic and therapeutic use |
EP3095461A4 (en) * | 2014-01-15 | 2017-08-23 | Shin Nippon Biomedical Laboratories, Ltd. | Chiral nucleic acid adjuvant having immunity induction activity, and immunity induction activator |
EP3095459A4 (en) * | 2014-01-15 | 2017-08-23 | Shin Nippon Biomedical Laboratories, Ltd. | Chiral nucleic acid adjuvant having antitumor effect and antitumor agent |
WO2015108046A1 (ja) * | 2014-01-15 | 2015-07-23 | 株式会社新日本科学 | 抗アレルギー作用を有するキラル核酸アジュバンド及び抗アレルギー剤 |
MY193116A (en) | 2014-01-16 | 2022-09-26 | Wave Life Sciences Ltd | Chiral design |
CN106535876B (zh) | 2014-06-04 | 2020-09-11 | 埃克西奎雷股份有限公司 | 免疫调节剂通过脂质体球形核酸的多价递送以用于预防或治疗应用 |
CN107208092B (zh) | 2014-12-16 | 2021-09-10 | 罗氏创新中心哥本哈根有限公司 | 手性毒性筛选方法 |
JP6715775B2 (ja) | 2014-12-25 | 2020-07-01 | 国立研究開発法人医薬基盤・健康・栄養研究所 | 非凝集性免疫賦活化オリゴヌクレオチド |
MA43072A (fr) | 2015-07-22 | 2018-05-30 | Wave Life Sciences Ltd | Compositions d'oligonucléotides et procédés associés |
CR20180233A (es) | 2015-10-09 | 2018-05-25 | Wave Life Sciences Ltd | Composiciones oligonucleotídicas y sus métodos |
MA43822A (fr) | 2016-03-13 | 2018-11-28 | Wave Life Sciences Ltd | Compositions et procédés de synthèse de phosphoramidite et d'oligonucléotides |
MA45270A (fr) | 2016-05-04 | 2017-11-09 | Wave Life Sciences Ltd | Compositions d'oligonucléotides et procédés associés |
CN109562122A (zh) | 2016-06-03 | 2019-04-02 | 波涛生命科学有限公司 | 寡核苷酸、组合物及其方法 |
WO2018039629A2 (en) | 2016-08-25 | 2018-03-01 | Northwestern University | Micellar spherical nucleic acids from thermoresponsive, traceless templates |
US11873316B2 (en) | 2016-11-23 | 2024-01-16 | Wave Life Sciences Ltd. | Compositions and methods for phosphoramidite and oligonucleotide synthesis |
CA3043768A1 (en) | 2016-11-29 | 2018-06-07 | PureTech Health LLC | Exosomes for delivery of therapeutic agents |
SG11201909516VA (en) | 2017-04-14 | 2019-11-28 | Tollnine Inc | Immunomodulating polynucleotides, antibody conjugates thereof, and methods of their use |
US11696954B2 (en) | 2017-04-28 | 2023-07-11 | Exicure Operating Company | Synthesis of spherical nucleic acids using lipophilic moieties |
CN110997692A (zh) | 2017-06-02 | 2020-04-10 | 波涛生命科学有限公司 | 寡核苷酸组合物及其使用方法 |
WO2018223056A1 (en) | 2017-06-02 | 2018-12-06 | Wave Life Sciences Ltd. | Oligonucleotide compositions and methods of use thereof |
US11718638B2 (en) | 2017-06-21 | 2023-08-08 | Wave Life Sciences Ltd. | Compounds, compositions and methods for synthesis |
EP3664815A4 (en) | 2017-08-08 | 2021-08-11 | Wave Life Sciences Ltd. | OLIGONUCLEOTIDIC COMPOSITIONS AND ASSOCIATED METHODS |
KR20200052369A (ko) | 2017-09-18 | 2020-05-14 | 웨이브 라이프 사이언시스 리미티드 | 올리고뉴클레오티드 제조 기술 |
US11596646B2 (en) | 2017-10-12 | 2023-03-07 | Wave Life Sciences Ltd. | Oligonucleotide compositions and methods thereof |
CN112004928A (zh) * | 2018-04-12 | 2020-11-27 | 波涛生命科学有限公司 | 寡核苷酸组合物及其使用方法 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000006588A1 (en) * | 1998-07-27 | 2000-02-10 | University Of Iowa Research Foundation | STEREOISOMERS OF CpG OLIGONUCLEOTIDES AND RELATED METHODS |
JP2001503267A (ja) * | 1996-10-30 | 2001-03-13 | ユニバーシティ オブ アイオワ リサーチ ファウンデーション | 免疫刺激性核酸分子 |
WO2001022990A2 (en) * | 1999-09-27 | 2001-04-05 | Coley Pharmaceutical Group, Inc. | Methods related to immunostimulatory nucleic acid-induced interferon |
CN1688192A (zh) * | 2002-08-19 | 2005-10-26 | 科勒制药集团有限公司 | 免疫刺激核酸 |
JP2006515277A (ja) * | 2002-10-29 | 2006-05-25 | コーリー ファーマシューティカル グループ, リミテッド | C型肝炎ウィルス感染の処置および予防に関する方法および製品 |
WO2007139190A1 (ja) * | 2006-05-31 | 2007-12-06 | Toray Industries, Inc. | 免疫刺激オリゴヌクレオチド及びその医薬用途 |
JP2008531018A (ja) * | 2005-02-24 | 2008-08-14 | コーリー ファーマシューティカル グループ,インコーポレイテッド | 免疫刺激性オリゴヌクレオチド |
Family Cites Families (477)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US450870A (en) | 1891-04-21 | Bag-fastening | ||
US2878264A (en) | 1959-03-17 | Substituted amino alcohols | ||
CH372667A (de) | 1957-09-26 | 1963-10-31 | Robins Co Inc A H | Verfahren zur Herstellung von 3-Aryl-3-pyrrolidinolen |
US3135766A (en) | 1961-10-03 | 1964-06-02 | Mead Johnson & Co | 3-substituted-3-pyrrolidinols |
US3484473A (en) | 1967-05-12 | 1969-12-16 | Buckman Labor Inc | Methylene bisesters of thiolsulfonic acids |
DE1934150A1 (de) | 1968-07-10 | 1970-01-15 | Pennwalt Corp | Neue 1-Alkanoyloxy-1,2,4,5-tetrahydro-3H,3-benzazepine |
US3854480A (en) | 1969-04-01 | 1974-12-17 | Alza Corp | Drug-delivery system |
US3687808A (en) | 1969-08-14 | 1972-08-29 | Univ Leland Stanford Junior | Synthetic polynucleotides |
US3745162A (en) | 1970-08-31 | 1973-07-10 | Robins Co Inc A H | 1,2,3,4-tetrahydroisoquinoline-2-(thio)-carboxamides |
GB1448437A (en) | 1973-02-24 | 1976-09-08 | Beecham Group Ltd | Diphenylpropylamines |
US4022791A (en) | 1975-06-03 | 1977-05-10 | Pfizer Inc. | 2-Aminomethyl-3,4-dihydronaphthalenes |
GB1504424A (en) | 1975-08-09 | 1978-03-22 | Beecham Group Ltd | Isoquinoline-derived aminoethers |
US4126252A (en) | 1977-06-14 | 1978-11-21 | Wasserman Arnold S | Foldable garment support frame |
BR7807288A (pt) | 1977-11-08 | 1979-06-12 | Genentech Inc | Processo para sintese de polinucleotidos |
DD133885B1 (de) | 1978-01-04 | 1981-02-25 | Hans Lehmann | Mittel zur bekaempfung von phytopathogenen bakterien und pilzen |
US4500707A (en) | 1980-02-29 | 1985-02-19 | University Patents, Inc. | Nucleosides useful in the preparation of polynucleotides |
US5132418A (en) | 1980-02-29 | 1992-07-21 | University Patents, Inc. | Process for preparing polynucleotides |
US4458066A (en) | 1980-02-29 | 1984-07-03 | University Patents, Inc. | Process for preparing polynucleotides |
US4383534A (en) | 1980-06-05 | 1983-05-17 | Peters Jeffrey L | Vital signs monitoring apparatus |
US4469863A (en) | 1980-11-12 | 1984-09-04 | Ts O Paul O P | Nonionic nucleic acid alkyl and aryl phosphonates and processes for manufacture and use thereof |
US4675189A (en) | 1980-11-18 | 1987-06-23 | Syntex (U.S.A.) Inc. | Microencapsulation of water soluble active polypeptides |
US4415732A (en) | 1981-03-27 | 1983-11-15 | University Patents, Inc. | Phosphoramidite compounds and processes |
US4973679A (en) | 1981-03-27 | 1990-11-27 | University Patents, Inc. | Process for oligonucleo tide synthesis using phosphormidite intermediates |
US4668777A (en) | 1981-03-27 | 1987-05-26 | University Patents, Inc. | Phosphoramidite nucleoside compounds |
AU568067B2 (en) | 1981-10-23 | 1987-12-17 | Molecular Biosystems, Inc. | Oligonucleotide therapeutic agent and methods of making same |
US5023243A (en) | 1981-10-23 | 1991-06-11 | Molecular Biosystems, Inc. | Oligonucleotide therapeutic agent and method of making same |
US4542142A (en) | 1982-11-22 | 1985-09-17 | Roussel Uclaf | Insecticidal cyclopropane carboxylic acid derivatives with 3-unsaturated-side chain |
US4452775A (en) | 1982-12-03 | 1984-06-05 | Syntex (U.S.A.) Inc. | Cholesterol matrix delivery system for sustained release of macromolecules |
DE3329892A1 (de) | 1983-08-18 | 1985-03-07 | Köster, Hubert, Prof. Dr., 2000 Hamburg | Verfahren zur herstellung von oligonucleotiden |
US5118800A (en) | 1983-12-20 | 1992-06-02 | California Institute Of Technology | Oligonucleotides possessing a primary amino group in the terminal nucleotide |
US4688815A (en) | 1984-03-27 | 1987-08-25 | Lectrolarm Custom Systems, Inc. | Hydraulically driven bicycle |
US5643889A (en) | 1984-07-11 | 1997-07-01 | Temple University-Of The Commonwealth System Of Pennsylvania | Cholesterol conjugates of 2'5'-oligoadenylate derivatives and antiviral uses thereof |
FR2567892B1 (fr) | 1984-07-19 | 1989-02-17 | Centre Nat Rech Scient | Nouveaux oligonucleotides, leur procede de preparation et leurs applications comme mediateurs dans le developpement des effets des interferons |
US5367066A (en) | 1984-10-16 | 1994-11-22 | Chiron Corporation | Oligonucleotides with selectably cleavable and/or abasic sites |
FR2575751B1 (fr) | 1985-01-08 | 1987-04-03 | Pasteur Institut | Nouveaux nucleosides de derives de l'adenosine, leur preparation et leurs applications biologiques |
FR2576898B1 (fr) | 1985-02-01 | 1988-01-08 | Lafon Labor | Derives de 3-phenyl-tetrahydropyridine, procede de preparation et utilisation en therapeutique |
US4659774A (en) | 1985-11-01 | 1987-04-21 | American Hoechst Corporation | Support for solid-phase oligonucleotide synthesis |
US4735949A (en) | 1986-02-18 | 1988-04-05 | Warner-Lambert Company | Disubstituted-7-pyrrolidinonaphthyridine antibacterial agents |
US4840956A (en) | 1986-02-18 | 1989-06-20 | Warner-Lambert Company | Novel disubstituted-7-pyrrolidinoquinoline antibacterial agents |
US5075109A (en) | 1986-10-24 | 1991-12-24 | Southern Research Institute | Method of potentiating an immune response |
IL83663A0 (en) | 1986-10-27 | 1988-01-31 | Robins Co Inc A H | Preparation of 3-pyrrolidinols |
DE3851889T2 (de) | 1987-06-24 | 1995-04-13 | Florey Howard Inst | Nukleosid-derivate. |
DE3884517T2 (de) | 1987-07-30 | 1994-02-10 | Kupat Holim Health Insurance | Biologisch aktive Carbonsäureester. |
US4923901A (en) | 1987-09-04 | 1990-05-08 | Millipore Corporation | Membranes with bound oligonucleotides and peptides |
US5175273A (en) | 1988-07-01 | 1992-12-29 | Genentech, Inc. | Nucleic acid intercalating agents |
CA1306722C (en) | 1988-09-29 | 1992-08-25 | Gabriel Sebastian | Shirt buttoner |
US5047524A (en) | 1988-12-21 | 1991-09-10 | Applied Biosystems, Inc. | Automated system for polynucleotide synthesis and purification |
US5262530A (en) | 1988-12-21 | 1993-11-16 | Applied Biosystems, Inc. | Automated system for polynucleotide synthesis and purification |
US5133974A (en) | 1989-05-05 | 1992-07-28 | Kv Pharmaceutical Company | Extended release pharmaceutical formulations |
JP2794461B2 (ja) | 1989-08-17 | 1998-09-03 | 有機合成薬品工業株式会社 | ホスホアミダイト化合物及びそれを用いたオリゴリボヌクレオチドの固相合成法 |
US5141813A (en) | 1989-08-28 | 1992-08-25 | Clontech Laboratories, Inc. | Multifunctional controlled pore glass reagent for solid phase oligonucleotide synthesis |
US5134066A (en) | 1989-08-29 | 1992-07-28 | Monsanto Company | Improved probes using nucleosides containing 3-dezauracil analogs |
CA2029273A1 (en) | 1989-12-04 | 1991-06-05 | Christine L. Brakel | Modified nucleotide compounds |
US5130302A (en) | 1989-12-20 | 1992-07-14 | Boron Bilogicals, Inc. | Boronated nucleoside, nucleotide and oligonucleotide compounds, compositions and methods for using same |
EP0507863A4 (en) | 1989-12-28 | 1993-07-07 | Virginia Commonwealth University | Sigma receptor ligands and the use thereof |
US5681941A (en) | 1990-01-11 | 1997-10-28 | Isis Pharmaceuticals, Inc. | Substituted purines and oligonucleotide cross-linking |
US5459255A (en) | 1990-01-11 | 1995-10-17 | Isis Pharmaceuticals, Inc. | N-2 substituted purines |
US5852188A (en) | 1990-01-11 | 1998-12-22 | Isis Pharmaceuticals, Inc. | Oligonucleotides having chiral phosphorus linkages |
US5914396A (en) | 1990-01-11 | 1999-06-22 | Isis Pharmaceuticals, Inc. | 2'-O-modified nucleosides and phosphoramidites |
US5635488A (en) | 1991-10-15 | 1997-06-03 | Isis Pharmaceuticals, Inc. | Compounds having phosphorodithioate linkages of high chiral purity |
US5587361A (en) | 1991-10-15 | 1996-12-24 | Isis Pharmaceuticals, Inc. | Oligonucleotides having phosphorothioate linkages of high chiral purity |
US5587470A (en) | 1990-01-11 | 1996-12-24 | Isis Pharmaceuticals, Inc. | 3-deazapurines |
DE69133405T2 (de) | 1990-01-11 | 2005-07-07 | Isis Pharmaceutical, Inc., Carlsbad | Oligonukleotidderivate zur detektieren und modulation von rna aktivität und genexpression |
US5620963A (en) | 1991-10-15 | 1997-04-15 | Isis Pharmaceuticals, Inc. | Oligonucleotides for modulating protein kinase C having phosphorothioate linkages of high chiral purity |
US5212295A (en) | 1990-01-11 | 1993-05-18 | Isis Pharmaceuticals | Monomers for preparation of oligonucleotides having chiral phosphorus linkages |
US6339066B1 (en) | 1990-01-11 | 2002-01-15 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotides which have phosphorothioate linkages of high chiral purity and which modulate βI, βII, γ, δ, Ε, ζ and η isoforms of human protein kinase C |
US5506212A (en) | 1990-01-11 | 1996-04-09 | Isis Pharmaceuticals, Inc. | Oligonucleotides with substantially chirally pure phosphorothioate linkages |
US5457191A (en) | 1990-01-11 | 1995-10-10 | Isis Pharmaceuticals, Inc. | 3-deazapurines |
US7101993B1 (en) | 1990-01-11 | 2006-09-05 | Isis Pharmaceuticals, Inc. | Oligonucleotides containing 2′-O-modified purines |
US5292875A (en) | 1990-04-20 | 1994-03-08 | Lynx Therapeutics, Inc. | Method of synthesizing sulfurized oligonucleotide analogs |
US5151510A (en) | 1990-04-20 | 1992-09-29 | Applied Biosystems, Inc. | Method of synethesizing sulfurized oligonucleotide analogs |
JPH06500075A (ja) | 1990-05-23 | 1994-01-06 | アイシス・ファーマシューティカルス・インコーポレーテッド | Rnaの5´キャップ構造の修飾によりrna活性を変調させるための組成物および方法 |
US5610289A (en) | 1990-07-27 | 1997-03-11 | Isis Pharmaceuticals, Inc. | Backbone modified oligonucleotide analogues |
EP0544824B1 (en) | 1990-07-27 | 1997-06-11 | Isis Pharmaceuticals, Inc. | Nuclease resistant, pyrimidine modified oligonucleotides that detect and modulate gene expression |
US5432272A (en) | 1990-10-09 | 1995-07-11 | Benner; Steven A. | Method for incorporating into a DNA or RNA oligonucleotide using nucleotides bearing heterocyclic bases |
US5512668A (en) | 1991-03-06 | 1996-04-30 | Polish Academy Of Sciences | Solid phase oligonucleotide synthesis using phospholane intermediates |
US7015315B1 (en) | 1991-12-24 | 2006-03-21 | Isis Pharmaceuticals, Inc. | Gapped oligonucleotides |
US6414112B1 (en) | 1991-05-24 | 2002-07-02 | Ole Buchardt | Peptide nucleic acids having 2,6-diaminopurine nucleobases |
JPH04348077A (ja) | 1991-05-24 | 1992-12-03 | Nec Corp | 薄膜トランジスタ |
TW360711B (en) | 1991-06-10 | 1999-06-11 | Lucky Ltd | CDNAs of Korean hepatitis C virus and polypeptides encoded thereby |
US5646267A (en) | 1991-08-05 | 1997-07-08 | Polish Academy Of Sciences | Method of making oligonucleotides and oligonucleotide analogs using phospholanes and enantiomerically resolved phospholane analogues |
US5359052A (en) | 1991-08-05 | 1994-10-25 | Polish Academy Of Sciences | Chalcophospholanes useful in the synthesis of oligonucleoside phosphorothioates, phosphorodithioates and related selenates |
US7119184B2 (en) | 1991-08-12 | 2006-10-10 | Isis Pharmaceuticals, Inc. | Oligonucleotides having A-DNA form and B-DNA form conformational geometry |
US6369209B1 (en) | 1999-05-03 | 2002-04-09 | Isis Pharmaceuticals, Inc. | Oligonucleotides having A-DNA form and B-DNA form conformational geometry |
CA2121144C (en) | 1991-10-15 | 2001-07-31 | Phillip Dan Cook | Oligonucleotides having chiral phosphorus linkages |
US5599797A (en) | 1991-10-15 | 1997-02-04 | Isis Pharmaceuticals, Inc. | Oligonucleotides having phosphorothioate linkages of high chiral purity |
US5576302A (en) | 1991-10-15 | 1996-11-19 | Isis Pharmaceuticals, Inc. | Oligonucleotides for modulating hepatitis C virus having phosphorothioate linkages of high chiral purity |
US5607923A (en) | 1991-10-15 | 1997-03-04 | Isis Pharmaceuticals, Inc. | Oligonucleotides for modulating cytomegalovirus having phosphorothioate linkages of high chiral purity |
US5661134A (en) | 1991-10-15 | 1997-08-26 | Isis Pharmaceuticals, Inc. | Oligonucleotides for modulating Ha-ras or Ki-ras having phosphorothioate linkages of high chiral purity |
US5654284A (en) | 1991-10-15 | 1997-08-05 | Isis Pharmaceuticals, Inc. | Oligonucleotides for modulating RAF kinase having phosphorothioate linkages of high chiral purity |
DE59208572D1 (de) | 1991-10-17 | 1997-07-10 | Ciba Geigy Ag | Bicyclische Nukleoside, Oligonukleotide, Verfahren zu deren Herstellung und Zwischenprodukte |
US5594121A (en) | 1991-11-07 | 1997-01-14 | Gilead Sciences, Inc. | Enhanced triple-helix and double-helix formation with oligomers containing modified purines |
US5484908A (en) | 1991-11-26 | 1996-01-16 | Gilead Sciences, Inc. | Oligonucleotides containing 5-propynyl pyrimidines |
US6235887B1 (en) | 1991-11-26 | 2001-05-22 | Isis Pharmaceuticals, Inc. | Enhanced triple-helix and double-helix formation directed by oligonucleotides containing modified pyrimidines |
US5407686A (en) | 1991-11-27 | 1995-04-18 | Sidmak Laboratories, Inc. | Sustained release composition for oral administration of active ingredient |
US5359044A (en) | 1991-12-13 | 1994-10-25 | Isis Pharmaceuticals | Cyclobutyl oligonucleotide surrogates |
ATE317848T1 (de) | 1991-12-24 | 2006-03-15 | Isis Pharmaceuticals Inc | Unterbrochene 2'-modifizierte oligonukleotide |
GB9213601D0 (en) | 1992-06-26 | 1992-08-12 | Mastico Robert A | Protein based delivery system |
US7067497B2 (en) | 1992-09-29 | 2006-06-27 | Isis Pharmaceuticals, Inc. | Modulation of telomere length by oligonucleotides having a G-core sequence |
CA2154578A1 (en) | 1993-01-25 | 1994-08-04 | Ekambar R. Kandimalla | Oligonucleotide alkylphosphonates and alkylphosphonothioates |
US5955591A (en) | 1993-05-12 | 1999-09-21 | Imbach; Jean-Louis | Phosphotriester oligonucleotides, amidites and method of preparation |
US6015886A (en) | 1993-05-24 | 2000-01-18 | Chemgenes Corporation | Oligonucleotide phosphate esters |
US5502177A (en) | 1993-09-17 | 1996-03-26 | Gilead Sciences, Inc. | Pyrimidine derivatives for labeled binding partners |
US5643989A (en) | 1993-10-29 | 1997-07-01 | Azdel, Inc. | Fiber reinforced functionalized polyolefin composites |
WO1998003542A1 (en) | 1996-07-24 | 1998-01-29 | Buchardt, Dorte | Peptide nucleic acids having enhanced binding affinity, sequence specificity and solubility |
US5457187A (en) | 1993-12-08 | 1995-10-10 | Board Of Regents University Of Nebraska | Oligonucleotides containing 5-fluorouracil |
DE4435728A1 (de) | 1994-01-19 | 1995-07-20 | Boehringer Mannheim Gmbh | Biotinsilan-Verbindungen und diese Verbindungen enthaltende Bindematrix |
US6117679A (en) | 1994-02-17 | 2000-09-12 | Maxygen, Inc. | Methods for generating polynucleotides having desired characteristics by iterative selection and recombination |
JP3553958B2 (ja) | 1994-02-22 | 2004-08-11 | ノボザイムス アクティーゼルスカブ | 脂質分解酵素の変異体の製造方法 |
US5596091A (en) | 1994-03-18 | 1997-01-21 | The Regents Of The University Of California | Antisense oligonucleotides comprising 5-aminoalkyl pyrimidine nucleotides |
BR9507678A (pt) | 1994-05-11 | 1997-09-23 | Novo Nordisk As | Construção de dna vetor de expressão recombinante célula proceso para produzir uma enzima enzima preparação de enzima uso da enzima e cultura |
US5525711A (en) | 1994-05-18 | 1996-06-11 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Pteridine nucleotide analogs as fluorescent DNA probes |
ES2320315T5 (es) | 1994-07-15 | 2012-12-05 | University Of Iowa Research Foundation | Oligonucleótidos inmunoestimuladores |
US6239116B1 (en) | 1994-07-15 | 2001-05-29 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
CA2199464A1 (en) | 1994-09-07 | 1996-03-14 | Radhakrishnan Iyer | Oligonucleotide prodrugs |
US5681940A (en) | 1994-11-02 | 1997-10-28 | Icn Pharmaceuticals | Sugar modified nucleosides and oligonucleotides |
WO1996019572A1 (en) | 1994-12-22 | 1996-06-27 | Hybridon, Inc. | Synthesis of stereospecific oligonucleotide phosphorothioates |
GB9501465D0 (en) | 1995-01-25 | 1995-03-15 | King S College London | Nucleoside phosphorothioate derivatives,synthesis and use thereof |
ATE327244T1 (de) | 1995-03-06 | 2006-06-15 | Isis Pharmaceuticals Inc | Verfahren zur synthese von 2'-0-substituierten pyrimidinen und oligomere davon |
US6166197A (en) | 1995-03-06 | 2000-12-26 | Isis Pharmaceuticals, Inc. | Oligomeric compounds having pyrimidine nucleotide (S) with 2'and 5 substitutions |
DE69638104D1 (de) | 1995-04-27 | 2010-02-11 | Takara Bio Inc | Für Lacto-N-biosidase kodierendes Gen |
ATE271128T1 (de) | 1995-05-11 | 2004-07-15 | Applied Research Systems | Inhibitoren der il-6 aktivitaet |
DK0836612T3 (da) | 1995-05-23 | 2000-10-30 | Hybridon Inc | Nye synthoner til stereoselektiv oligonucleotidsyntese |
AU5871196A (en) | 1995-05-23 | 1996-12-24 | Hybridon, Inc. | Methods and compounds for the synthesis of oligonucleotides and the oligonucleotides thereby produced |
WO1996039154A1 (en) | 1995-06-06 | 1996-12-12 | Isis Pharmaceuticals, Inc. | Oligonucleotides having phosphorothioate linkages of high chiral purity |
US5932450A (en) | 1995-06-07 | 1999-08-03 | Gen-Probe Incorporated | Enzymatic synthesis of oligonucleotides using digestible templates |
DE69635849T2 (de) | 1995-06-29 | 2006-10-19 | Takara Bio Inc., Otsu | Für Endoglycoceramidase kodierendes Gen |
DE69636649T2 (de) | 1995-06-29 | 2007-10-04 | Takara Bio Inc., Otsu | Für einen Endoglycoceramidase-Aktivator kodierendes Gen |
US6017700A (en) | 1995-08-04 | 2000-01-25 | Bayer Corporation | Cationic oligonucleotides, and related methods of synthesis and use |
US5936080A (en) | 1996-05-24 | 1999-08-10 | Genta Incorporated | Compositions and methods for the synthesis of organophosphorus derivatives |
US6160109A (en) | 1995-10-20 | 2000-12-12 | Isis Pharmaceuticals, Inc. | Preparation of phosphorothioate and boranophosphate oligomers |
US6476216B1 (en) | 1995-10-20 | 2002-11-05 | Mcgill University | Preparation of phosphorothioate oligomers |
US5734041A (en) | 1995-10-20 | 1998-03-31 | Mcgill University | Preparation of chiral phosphorothioate oligomers |
US5736152A (en) | 1995-10-27 | 1998-04-07 | Atrix Laboratories, Inc. | Non-polymeric sustained release delivery system |
US7018793B1 (en) | 1995-12-07 | 2006-03-28 | Diversa Corporation | Combinatorial screening of mixed populations of organisms |
JP2000506384A (ja) | 1996-02-15 | 2000-05-30 | ナショナル インスティチューツ オブ ヘルス | RNase L アクチベーター及びRSV感染の治療に有効なアンチセンスオリゴヌクレオチド |
US6214805B1 (en) | 1996-02-15 | 2001-04-10 | The United States Of America As Represented By The Department Of Health And Human Services | RNase L activators and antisense oligonucleotides effective to treat RSV infections |
GB9604669D0 (en) | 1996-03-05 | 1996-05-01 | Ciba Geigy Ag | Chemical compounds |
US5824669A (en) | 1996-03-22 | 1998-10-20 | Nitromed, Inc. | Nitrosated and nitrosylated compounds and compositions and their use for treating respiratory disorders |
EP0898618B1 (en) | 1996-05-10 | 2007-10-31 | Novozymes A/S | Method of providing novel dna sequences |
US5856465A (en) | 1996-05-24 | 1999-01-05 | Polska Akademia Nauk Centrum Badan Molekularnych I Makromolekularnych | Compositions and methods for the synthesis of chirally pure organophosphorus nucleoside derivatives |
US5898031A (en) | 1996-06-06 | 1999-04-27 | Isis Pharmaceuticals, Inc. | Oligoribonucleotides for cleaving RNA |
DE19622783A1 (de) | 1996-06-07 | 1997-12-11 | Hoechst Ag | Isolierung der Biosynthesegene für Pseudo-Oligosaccharide aus Streptomyces glaucescens GLA.O und ihre Verwendung |
AU726821B2 (en) | 1996-07-16 | 2000-11-23 | Gen-Probe Incorporated | Methods for detecting and amplifying nucleic acid sequences using modified oligonucleotides having increased target specific Tm |
US5912332A (en) | 1996-07-26 | 1999-06-15 | Hybridon, Inc. | Affinity-based purification of oligonucleotides using soluble multimeric oligonucleotides |
AU4156197A (en) | 1996-08-21 | 1998-03-06 | Hybridon, Inc. | Oligonucleotide prodrugs |
US6056973A (en) | 1996-10-11 | 2000-05-02 | Sequus Pharmaceuticals, Inc. | Therapeutic liposome composition and method of preparation |
US6639062B2 (en) | 1997-02-14 | 2003-10-28 | Isis Pharmaceuticals, Inc. | Aminooxy-modified nucleosidic compounds and oligomeric compounds prepared therefrom |
US6369237B1 (en) | 1997-03-07 | 2002-04-09 | President And Fellows Of Harvard College | DNA glycosylase inhibitors, and uses related thereto |
US6015887A (en) | 1997-04-11 | 2000-01-18 | Isis Pharmaceuticals, Inc. | Chiral peptide nucleic acids and methods for preparing same |
US6468983B2 (en) | 1997-04-21 | 2002-10-22 | The Cleveland Clinic Foundation | RNase L activators and antisense oligonucleotides effective to treat telomerase-expressing malignancies |
PL184612B1 (pl) | 1997-04-25 | 2002-11-29 | Pan | Sposób wytwarzania modyfikowanych P chiralnych analogów nukleotydów |
EP1003480A4 (en) | 1997-05-28 | 2002-04-17 | Nielsen Peter Eigil | NUCLEIC ACIDS CONJUGED WITH PEPTIDES WITH INCREASED UPDATE IN CELLS |
WO1999005160A2 (en) | 1997-07-25 | 1999-02-04 | Hybridon, Inc. | Oligonuclotides having 3' terminal stereospecific phosphorothioates |
US6767739B2 (en) | 2001-07-30 | 2004-07-27 | Isis Pharmaceuticals Inc. | Antisense modulation of microsomal triglyceride transfer protein expression |
GB9717158D0 (en) | 1997-08-13 | 1997-10-22 | King S College London | Solution synthesis of oligonucleotides and their phosphorothioate analogues |
US6383808B1 (en) | 2000-09-11 | 2002-05-07 | Isis Pharmaceuticals, Inc. | Antisense inhibition of clusterin expression |
US6750344B1 (en) | 1997-09-05 | 2004-06-15 | Isis Pharmaceuticals, Inc. | Amine compounds and combinatorial libraries comprising same |
DE19741715A1 (de) | 1997-09-22 | 1999-03-25 | Hoechst Ag | Pentopyranosyl-Nucleosid, seine Herstellung und Verwendung |
US6617438B1 (en) | 1997-11-05 | 2003-09-09 | Sirna Therapeutics, Inc. | Oligoribonucleotides with enzymatic activity |
US6528640B1 (en) | 1997-11-05 | 2003-03-04 | Ribozyme Pharmaceuticals, Incorporated | Synthetic ribonucleic acids with RNAse activity |
US6080543A (en) | 1997-12-08 | 2000-06-27 | E. & J. Gallo Winery | Detection of fungal pathogens |
US6582936B1 (en) | 1997-12-12 | 2003-06-24 | The Regents Of The University Of California | Methods for making nucleic acids |
US6248519B1 (en) | 1998-03-11 | 2001-06-19 | E & J Gallo Winery | Detection of fermentation-related microorganisms |
US7045610B2 (en) | 1998-04-03 | 2006-05-16 | Epoch Biosciences, Inc. | Modified oligonucleotides for mismatch discrimination |
CA2328602A1 (en) | 1998-05-06 | 1999-11-11 | University Of Iowa Research Foundation | Methods for the prevention and treatment of parasitic infections and related diseases using cpg oligonucleotides |
EP1674574A1 (en) | 1998-05-14 | 2006-06-28 | Coley Pharmaceutical GmbH | Methods for Regulating Hematopoiesis using CpG-Oligonucleotides |
US6242589B1 (en) | 1998-07-14 | 2001-06-05 | Isis Pharmaceuticals, Inc. | Phosphorothioate oligonucleotides having modified internucleoside linkages |
US6867294B1 (en) | 1998-07-14 | 2005-03-15 | Isis Pharmaceuticals, Inc. | Gapped oligomers having site specific chiral phosphorothioate internucleoside linkages |
WO2000023444A1 (en) | 1998-10-21 | 2000-04-27 | Abbott Laboratories | 5,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds |
US6995259B1 (en) | 1998-10-23 | 2006-02-07 | Sirna Therapeutics, Inc. | Method for the chemical synthesis of oligonucleotides |
US6451524B1 (en) | 1998-11-25 | 2002-09-17 | Isis Pharmaceuticals, Inc. | Identification of disease predictive nucleic acids |
WO2000031110A1 (en) | 1998-11-25 | 2000-06-02 | Isis Pharmaceuticals, Inc. | Identification of disease predictive nucleic acids |
US6379942B1 (en) | 1998-12-21 | 2002-04-30 | Genencor International, Inc. | Chemically modified enzymes with multiple charged variants |
AU1853600A (en) | 1999-01-06 | 2000-07-24 | Choong-Chin Liew | Method for the detection of gene transcripts in blood and uses thereof |
US6265172B1 (en) | 1999-02-08 | 2001-07-24 | University Of Kentucky | Diagnostic test and therapy for manganese superoxide dismutate (mNsod) associated diseases |
US6121437A (en) | 1999-03-16 | 2000-09-19 | Isis Pharmaceuticals, Inc. | Phosphate and thiophosphate protecting groups |
US6506594B1 (en) | 1999-03-19 | 2003-01-14 | Cornell Res Foundation Inc | Detection of nucleic acid sequence differences using the ligase detection reaction with addressable arrays |
GB9907245D0 (en) | 1999-03-29 | 1999-05-26 | Goldsborough Andrew | Cleavage of nucleic acids from solid supports |
US6977245B2 (en) * | 1999-04-12 | 2005-12-20 | The United States Of America As Represented By The Department Of Health And Human Services | Oligodeoxynucleotide and its use to induce an immune response |
US6300069B1 (en) | 1999-05-03 | 2001-10-09 | Qiagen Gmbh | Generation and amplification of nucleic acids from ribonucleic acids |
US6599912B1 (en) | 1999-06-03 | 2003-07-29 | Jessie L. -S. Au | Methods and compositions for modulating cell proliferation and cell death |
US6656730B1 (en) | 1999-06-15 | 2003-12-02 | Isis Pharmaceuticals, Inc. | Oligonucleotides conjugated to protein-binding drugs |
US6066500A (en) | 1999-06-25 | 2000-05-23 | Isis Pharmaceuticals Inc. | Antisense modulation of Beta catenin expression |
US6271004B1 (en) | 1999-06-25 | 2001-08-07 | Display Systems Biotech A/S | Method for improved reverse transcription at high temperatures |
US6414135B1 (en) | 1999-07-07 | 2002-07-02 | Isis Pharmaceuticals, Inc. | C3′-methylene hydrogen phosphonate monomers and related compounds |
US20030092647A1 (en) | 2001-08-08 | 2003-05-15 | Crooke Rosanne M. | Antisense modulation of cholesteryl ester transfer protein expression |
US6147200A (en) | 1999-08-19 | 2000-11-14 | Isis Pharmaceuticals, Inc. | 2'-O-acetamido modified monomers and oligomers |
US7264932B2 (en) | 1999-09-24 | 2007-09-04 | Applera Corporation | Nuclease inhibitor cocktail |
TR200503031T2 (tr) * | 1999-09-25 | 2005-09-21 | University Of Iowa Research Foundation | İmmünostimülatör nükleik asitler |
US6949520B1 (en) | 1999-09-27 | 2005-09-27 | Coley Pharmaceutical Group, Inc. | Methods related to immunostimulatory nucleic acid-induced interferon |
US20020082227A1 (en) | 1999-09-30 | 2002-06-27 | Scott Henry | Use of oligonucleotides for inhibition of complement activation |
AU7863200A (en) | 1999-10-06 | 2001-05-10 | Quark Biotech, Inc. | Method for enrichment of natural antisense messenger rna |
GB9924285D0 (en) | 1999-10-14 | 1999-12-15 | Avecia Ltd | Process |
US20010055761A1 (en) | 1999-10-29 | 2001-12-27 | Agilent Technologies | Small scale dna synthesis using polymeric solid support with functionalized regions |
FR2800750B1 (fr) | 1999-11-05 | 2003-01-31 | Centre Nat Rech Scient | Proteines membranaires ctl (choline transporter like) impliquees dans le transport de la choline |
WO2001040515A1 (en) | 1999-11-12 | 2001-06-07 | Isis Pharmaceuticals, Inc. | Gapped oligomers having site specific chiral phosphorothioate internucleoside linkages |
US6322985B1 (en) | 1999-12-27 | 2001-11-27 | Technion Research And Development Foundation Ltd. | Abundant, well distributed and hyperpolymorphic simple sequence repeats in prokaryote genomes and use of same for prokaryote classification and typing |
US7055094B2 (en) | 1999-12-30 | 2006-05-30 | Rutgers, The State University Of New Jersey | Virtual tags and the process of virtual tagging utilizing user feedback in transformation rules |
JP2004510953A (ja) | 1999-12-30 | 2004-04-08 | キャボット コーポレイション | 改良された性質を有するセンサー |
US6649750B1 (en) | 2000-01-05 | 2003-11-18 | Isis Pharmaceuticals, Inc. | Process for the preparation of oligonucleotide compounds |
US6159697A (en) | 2000-01-19 | 2000-12-12 | Isis Pharmaceuticals, Inc. | Antisense modulation of Smad7 expression |
US7585847B2 (en) * | 2000-02-03 | 2009-09-08 | Coley Pharmaceutical Group, Inc. | Immunostimulatory nucleic acids for the treatment of asthma and allergy |
CA2335389A1 (en) | 2000-03-01 | 2001-09-01 | Message Pharmaceuticals, Inc. | Novel bacterial rnase p proteins and their use in identifying antibacterial compounds |
GB0004889D0 (en) | 2000-03-01 | 2000-04-19 | Avecia Ltd | Synthesis of oligonucleotides |
WO2001070663A2 (en) * | 2000-03-17 | 2001-09-27 | Corixa Corporation | Novel amphipathic aldehydes and their use as adjuvants and immunoeffectors |
BR0110112A (pt) | 2000-04-20 | 2003-02-11 | Hoffmann La Roche | Derivados de pirrolidina e piperidina e seu uso para o tratamento de distúrbios neurodegenerativos |
WO2001085751A1 (en) | 2000-05-09 | 2001-11-15 | Reliable Biopharmaceutical, Inc. | Polymeric compounds useful as prodrugs |
US6492171B2 (en) | 2000-05-16 | 2002-12-10 | Isis Pharmaceuticals, Inc. | Antisense modulation of TERT expression |
KR100824075B1 (ko) | 2000-07-28 | 2008-04-22 | 이뮤파름 에이피에스 | 일반 감기, 알레르기성 비염 및 호흡기에 관련된 감염 증상의 치료 방법 |
US6809195B1 (en) | 2000-08-16 | 2004-10-26 | Isis Pharmaceuticals, Inc. | Process for the preparation of oligonucleotides |
US6559279B1 (en) | 2000-09-08 | 2003-05-06 | Isis Pharmaceuticals, Inc. | Process for preparing peptide derivatized oligomeric compounds |
EP1191097A1 (en) | 2000-09-21 | 2002-03-27 | Leids Universitair Medisch Centrum | Induction of exon skipping in eukaryotic cells |
GB0024752D0 (en) | 2000-10-10 | 2000-11-22 | Univ Belfast | Oxidative halogenation of aromatic compounds |
SI1326638T1 (sl) * | 2000-10-18 | 2008-04-30 | Glaxosmithkline Biolog Sa | Cepiva proti rakom |
US6682889B1 (en) | 2000-11-08 | 2004-01-27 | Becton, Dickinson And Company | Amplification and detection of organisms of the Chlamydiaceae family |
JP3888572B2 (ja) | 2000-11-22 | 2007-03-07 | マツダ株式会社 | 車両の周囲情報表示装置 |
SI1355916T1 (sl) | 2001-01-22 | 2007-04-30 | Merck & Co Inc | Nukleozidni derivati kot inhibitorji RNA-odvisne RNA virusne polimeraze |
AU2002227883A1 (en) | 2001-01-25 | 2002-08-06 | Evolva Biotech A/S | A library of a collection of cells |
US8008459B2 (en) | 2001-01-25 | 2011-08-30 | Evolva Sa | Concatemers of differentially expressed multiple genes |
CA2429397C (en) | 2001-01-26 | 2014-06-03 | Commonwealth Scientific And Industrial Research Organisation | Methods and means for producing efficient silencing construct using recombinational cloning |
US20050277133A1 (en) | 2001-05-18 | 2005-12-15 | Sirna Therapeutics, Inc. | RNA interference mediated treatment of polyglutamine (polyQ) repeat expansion diseases using short interfering nucleic acid (siNA) |
WO2002097134A2 (en) | 2001-05-25 | 2002-12-05 | Isis Pharmaceuticals, Inc. | Modified peptide nucleic acid |
GB0113523D0 (en) | 2001-06-04 | 2001-07-25 | Torotrak Dev Ltd | An Hydraulic control circuit for a continuosly variable transmission |
NZ530632A (en) * | 2001-06-29 | 2007-04-27 | Chiron Corp | HCV E1E2 vaccine compositions comprising E1E2 antigens, submicron oil-in-water emulsions and/or CpG oligonucleotides |
WO2003004602A2 (en) | 2001-07-03 | 2003-01-16 | Isis Pharmaceuticals, Inc. | Nuclease resistant chimeric oligonucleotides |
US7205399B1 (en) | 2001-07-06 | 2007-04-17 | Sirna Therapeutics, Inc. | Methods and reagents for oligonucleotide synthesis |
US7425545B2 (en) | 2001-07-25 | 2008-09-16 | Isis Pharmaceuticals, Inc. | Modulation of C-reactive protein expression |
US7888324B2 (en) | 2001-08-01 | 2011-02-15 | Genzyme Corporation | Antisense modulation of apolipoprotein B expression |
US7407943B2 (en) | 2001-08-01 | 2008-08-05 | Isis Pharmaceuticals, Inc. | Antisense modulation of apolipoprotein B expression |
US6455308B1 (en) | 2001-08-01 | 2002-09-24 | Isis Pharmaceuticals, Inc. | Antisense modulation of serum amyloid A4 expression |
CA2456328C (en) | 2001-08-07 | 2015-05-26 | Dynavax Technologies Corporation | Complexes of a short cpg-containing oligonucleotide bound to the surface of a solid phase microcarrier and methods for use thereof |
US7227014B2 (en) | 2001-08-07 | 2007-06-05 | Isis Pharmaceuticals, Inc. | Antisense modulation of apolipoprotein (a) expression |
US7259150B2 (en) | 2001-08-07 | 2007-08-21 | Isis Pharmaceuticals, Inc. | Modulation of apolipoprotein (a) expression |
US7354909B2 (en) * | 2001-08-14 | 2008-04-08 | The United States Of America As Represented By Secretary Of The Department Of Health And Human Services | Method for rapid generation of mature dendritic cells |
PT1446162E (pt) | 2001-08-17 | 2009-01-27 | Coley Pharm Gmbh | Agrupamentos imunoestimuladores oligonucléotidos com actividade melhorada |
US7049122B2 (en) | 2001-09-21 | 2006-05-23 | Academia Sinica | Mutant-type lipases and applications thereof |
US6933288B2 (en) | 2002-02-04 | 2005-08-23 | Isis Pharmaceuticals, Inc. | Pyranosyl cytosines: pharmaceutical formulations and methods |
JP4348044B2 (ja) | 2002-02-12 | 2009-10-21 | 株式会社キラルジェン | 立体規則性の高いジヌクレオシドホスホロチオエートの製造法 |
US20050096284A1 (en) | 2002-02-20 | 2005-05-05 | Sirna Therapeutics, Inc. | RNA interference mediated treatment of polyglutamine (polyQ) repeat expansion diseases using short interfering nucleic acid (siNA) |
US8232383B2 (en) | 2002-02-20 | 2012-07-31 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
US7288376B2 (en) | 2002-03-22 | 2007-10-30 | Council Of Scientific And Industrial Research | Method of detection of SP-A2 gene variants useful for prediction of predisposition to aspergillosis |
US20040102394A1 (en) | 2002-11-23 | 2004-05-27 | Isis Pharmaceuticals Inc. | Modulation of huntingtin interacting protein 2 expression |
AU2003237875A1 (en) | 2002-05-15 | 2003-12-02 | Isis Pharmaceuticals, Inc. | Antisense modulation of apolipoprotein b expression |
US20040014108A1 (en) | 2002-05-24 | 2004-01-22 | Eldrup Anne B. | Oligonucleotides having modified nucleoside units |
AU2003237249A1 (en) | 2002-05-24 | 2003-12-12 | Isis Pharmaceuticals, Inc. | Oligonucleotides having modified nucleoside units |
US7507808B2 (en) | 2002-12-12 | 2009-03-24 | Isis Pharmaceuticals, Inc. | Modulation of endothelial lipase expression |
WO2003106477A1 (en) | 2002-06-01 | 2003-12-24 | Isis Pharmaceuticals, Inc. | Oligomeric compounds that include carbocyclic nucleosides and their use in gene modulation |
MXPA04011210A (es) * | 2002-06-20 | 2005-02-14 | Cytos Biotechnology Ag | Particulares similares a virus empacadas para uso como adyuvantes: metodo de preparacion y uso. |
EP1520022B1 (en) | 2002-07-10 | 2015-07-22 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Rna-interference by single-stranded rna molecules |
US20040023905A1 (en) | 2002-07-31 | 2004-02-05 | Isis Pharmaceuticals Inc. | Antisense modulation of LAR expression |
US20050255086A1 (en) | 2002-08-05 | 2005-11-17 | Davidson Beverly L | Nucleic acid silencing of Huntington's Disease gene |
US20080274989A1 (en) | 2002-08-05 | 2008-11-06 | University Of Iowa Research Foundation | Rna Interference Suppression of Neurodegenerative Diseases and Methods of Use Thereof |
US20050042646A1 (en) | 2002-08-05 | 2005-02-24 | Davidson Beverly L. | RNA interference suppresion of neurodegenerative diseases and methods of use thereof |
US8729036B2 (en) | 2002-08-07 | 2014-05-20 | University Of Massachusetts | Compositions for RNA interference and methods of use thereof |
AR040996A1 (es) * | 2002-08-19 | 2005-04-27 | Coley Pharm Group Inc | Acidos nucleicos inmunoestimuladores |
US7414116B2 (en) | 2002-08-23 | 2008-08-19 | Illumina Cambridge Limited | Labelled nucleotides |
JP2005538186A (ja) | 2002-09-13 | 2005-12-15 | レプリコール インコーポレーティッド | 非配列相補性の抗ウイルス性オリゴヌクレオチド |
WO2004044141A2 (en) | 2002-11-05 | 2004-05-27 | Isis Pharmaceuticals, Inc. | Conjugated oligomeric compounds and their use in gene modulation |
WO2004044134A2 (en) | 2002-11-05 | 2004-05-27 | Isis Pharmaceuticals, Inc. | Phosphorous-linked oligomeric compounds and their use in gene modulation |
CA2504929C (en) | 2002-11-05 | 2014-07-22 | Charles Allerson | Compositions comprising alternating 2'-modified nucleosides for use in gene modulation |
EP1562971B1 (en) | 2002-11-05 | 2014-02-12 | Isis Pharmaceuticals, Inc. | Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation |
US7381527B2 (en) | 2002-11-06 | 2008-06-03 | Council Of Scientific And Industrial Research | Method of detection of SP-A2 gene variants |
US7511131B2 (en) | 2002-11-13 | 2009-03-31 | Genzyme Corporation | Antisense modulation of apolipoprotein B expression |
WO2004044181A2 (en) | 2002-11-13 | 2004-05-27 | Isis Pharmaceuticals, Inc. | Antisense modulation of apolipoprotein b expression |
DK2216407T3 (en) | 2003-03-07 | 2016-03-29 | Alnylam Pharmaceuticals Inc | therapeutic compositions |
CA2524255C (en) | 2003-03-21 | 2014-02-11 | Academisch Ziekenhuis Leiden | Modulation of exon recognition in pre-mrna by interfering with the secondary rna structure |
GB0306657D0 (en) | 2003-03-24 | 2003-04-30 | Avecia Ltd | Process and compounds |
CA2517839A1 (en) | 2003-03-26 | 2004-10-07 | Martin F. Bachmann | Melan-a peptide analogue-virus-like-particle conjugates |
US7537767B2 (en) | 2003-03-26 | 2009-05-26 | Cytis Biotechnology Ag | Melan-A- carrier conjugates |
ITRM20030149A1 (it) | 2003-04-02 | 2004-10-03 | Giuliani Spa | Oligonucleotidi (odn) antisenso per smad7 e loro usi in campo medico |
US7598227B2 (en) | 2003-04-16 | 2009-10-06 | Isis Pharmaceuticals Inc. | Modulation of apolipoprotein C-III expression |
US7045306B2 (en) | 2003-04-28 | 2006-05-16 | The General Hospital Corporation | Method for identifying compounds in vitro that modulate the dysregulation of transcription of transcription mediated by mutant huntingtin protein |
US7214491B2 (en) | 2003-05-07 | 2007-05-08 | E. I. Du Pont De Nemours And Company | Δ-12 desaturase gene suitable for altering levels of polyunsaturated fatty acids in oleaginous yeasts |
US7589189B2 (en) | 2003-05-14 | 2009-09-15 | Japan Science And Technology Agency | Inhibition of the expression of huntingtin gene |
EP1633307A4 (en) | 2003-06-03 | 2009-06-24 | Isis Pharmaceuticals Inc | MODULATION OF SURVIVIN EXPRESSION |
WO2005007672A2 (en) * | 2003-06-20 | 2005-01-27 | Coley Pharmaceutical Gmbh | Small molecule toll-like receptor (tlr) antagonists |
EP2216342B1 (en) | 2003-07-31 | 2015-04-22 | Immunomedics, Inc. | Anti-CD19 antibodies |
US7683036B2 (en) | 2003-07-31 | 2010-03-23 | Regulus Therapeutics Inc. | Oligomeric compounds and compositions for use in modulation of small non-coding RNAs |
JP2011088935A (ja) | 2003-08-08 | 2011-05-06 | Chiralgen Ltd | リン原子修飾ヌクレオチド類縁体の製造のための光学活性ヌクレオシド3’−ホスホロアミダイト |
JP2005089441A (ja) | 2003-08-08 | 2005-04-07 | Toudai Tlo Ltd | 立体規則性の高いリン原子修飾ヌクレオチド類縁体の製造法 |
US7825235B2 (en) | 2003-08-18 | 2010-11-02 | Isis Pharmaceuticals, Inc. | Modulation of diacylglycerol acyltransferase 2 expression |
US7427672B2 (en) | 2003-08-28 | 2008-09-23 | Takeshi Imanishi | Artificial nucleic acids of n-o bond crosslinkage type |
JP4616175B2 (ja) | 2003-09-02 | 2011-01-19 | 株式会社キラルジェン | 5’−ホスフィチル化モノマーおよびh−ホスホネートオリゴヌクレオチド誘導体の製造方法 |
JP4580870B2 (ja) | 2003-09-02 | 2010-11-17 | 株式会社キラルジェン | リボヌクレオチド又はリボヌクレオチド誘導体の製造方法 |
US20050053981A1 (en) | 2003-09-09 | 2005-03-10 | Swayze Eric E. | Gapped oligomeric compounds having linked bicyclic sugar moieties at the termini |
US20050074801A1 (en) | 2003-09-09 | 2005-04-07 | Monia Brett P. | Chimeric oligomeric compounds comprising alternating regions of northern and southern conformational geometry |
CA2579638C (en) | 2003-09-12 | 2016-04-19 | University Of Massachusetts | Rna interference targeting non-disease causing single nucleotide polymorphisms within a gene encoding a gain-of-function mutant huntingtin protein |
US8680063B2 (en) | 2003-09-12 | 2014-03-25 | University Of Massachusetts | RNA interference for the treatment of gain-of-function disorders |
GB0323968D0 (en) * | 2003-10-13 | 2003-11-19 | Glaxosmithkline Biolog Sa | Immunogenic compositions |
NZ546275A (en) * | 2003-10-30 | 2009-05-31 | Coley Pharm Gmbh | C-class oligonucleotides analogs with enhanced immunostimulatory potency |
US20050239102A1 (en) | 2003-10-31 | 2005-10-27 | Verdine Gregory L | Nucleic acid binding oligonucleotides |
US7846436B2 (en) | 2003-11-28 | 2010-12-07 | Chemgenes Corporation | Oligonucleotides and related compounds |
JP4945129B2 (ja) | 2004-01-27 | 2012-06-06 | 株式会社キラルジェン | フルオラス担体およびそれを用いたオリゴヌクレオチド誘導体の製造方法 |
WO2005076744A2 (en) | 2004-02-18 | 2005-08-25 | Frutarom Ltd. | Method for the preparation of peptide-oligonucleotide conjugates |
JP3976742B2 (ja) * | 2004-02-27 | 2007-09-19 | 江守商事株式会社 | インターフェロンアルファを誘導する免疫刺激オリゴヌクレオチド |
WO2005085272A1 (ja) | 2004-03-05 | 2005-09-15 | Takeshi Wada | ボラノホスフェートモノマーおよびそれを用いたオリゴヌクレオチド誘導体の製造方法 |
JP4865544B2 (ja) | 2004-03-25 | 2012-02-01 | 株式会社キラルジェン | 立体規則性の高いリボヌクレオチド類縁体及びデオキシリボヌクレオチド類縁体の製造法 |
US20050244869A1 (en) | 2004-04-05 | 2005-11-03 | Brown-Driver Vickie L | Modulation of transthyretin expression |
TWI350168B (en) | 2004-05-07 | 2011-10-11 | Incyte Corp | Amido compounds and their use as pharmaceuticals |
AU2005248410B2 (en) | 2004-05-27 | 2010-04-22 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Differential expression of molecules associated with acute stroke |
US7759318B1 (en) | 2004-05-28 | 2010-07-20 | Isis Pharmaceuticals, Inc. | Identification of novel pathways, genes and promoter motifs regulating adipogenesis |
PL2409713T3 (pl) | 2004-08-10 | 2016-02-29 | Kastle Therapeutics Llc | Oligonukleotydy do zastosowania w modulowaniu poziomów lipoproteiny i cholesterolu u ludzi |
ES2386709T3 (es) | 2004-08-26 | 2012-08-27 | Nippon Shinyaku Co., Ltd. | Compuesto de fosforamidita y método para producir un oligo-ARN |
US20070066551A1 (en) | 2004-09-07 | 2007-03-22 | Keefe Anthony D | Aptamer medicinal chemistry |
US7884086B2 (en) | 2004-09-08 | 2011-02-08 | Isis Pharmaceuticals, Inc. | Conjugates for use in hepatocyte free uptake assays |
US20090203132A1 (en) | 2004-09-09 | 2009-08-13 | Swayze Eric E | Pyrrolidinyl groups for attaching conjugates to oligomeric compounds |
EP2397563A3 (en) | 2004-09-17 | 2012-07-18 | Isis Pharmaceuticals, Inc. | Enhanced antisense oligonucleotides |
JP4944034B2 (ja) | 2004-10-13 | 2012-05-30 | アイシス ファーマシューティカルズ, インコーポレーテッド | Ptp1b発現のアンチセンス調節 |
KR100721928B1 (ko) | 2004-11-05 | 2007-05-28 | 주식회사 바이오씨에스 | CpG 올리고데옥시뉴클레오티드를 함유하는 피부질환의치료 또는 예방용 약학적 조성물 |
AU2005313883B2 (en) * | 2004-12-09 | 2011-03-31 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inducing an immune response in a mammal and methods of avoiding an immune response to oligonucleotide agents such as short interfering RNAs |
WO2006065751A2 (en) | 2004-12-13 | 2006-06-22 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Cpg oligonucleotide prodrugs, compositions thereof and associated therapeutic methods |
WO2006066260A2 (en) | 2004-12-17 | 2006-06-22 | Thiosense, Inc. | Compositions of and methods for producing phosphorus-chiral monomers and oligomers |
US20060183763A1 (en) | 2004-12-31 | 2006-08-17 | Pfizer Inc | Novel pyrrolidyl derivatives of heteroaromatic compounds |
EP1841777B1 (en) * | 2005-01-28 | 2015-09-30 | Kwon, Hyung-Joo | Oligonucleotides derived from mycobacterium for stimulating immune function, treating immune-related diseases, atopic dermatitis and/or protecting normal immune cell |
PT1877070E (pt) | 2005-05-05 | 2009-03-13 | Antisense Pharma Gmbh | Utilização terapêutica de oligonucleótidos anti-sentido tgf-beta2 |
EP1885854B1 (en) | 2005-05-06 | 2012-10-17 | Medtronic, Inc. | Methods and sequences to suppress primate huntington gene expression |
US7902352B2 (en) | 2005-05-06 | 2011-03-08 | Medtronic, Inc. | Isolated nucleic acid duplex for reducing huntington gene expression |
ATE522626T1 (de) | 2005-06-28 | 2011-09-15 | Medtronic Inc | Verfahren und nukleotid-sequenzen, die bevorzugt die expression eines mutierten huntingtin-genes unterdrücken |
US9133517B2 (en) | 2005-06-28 | 2015-09-15 | Medtronics, Inc. | Methods and sequences to preferentially suppress expression of mutated huntingtin |
WO2007005941A2 (en) | 2005-07-05 | 2007-01-11 | President And Fellows Of Harvard College | Liver targeted conjugates |
JP4984634B2 (ja) | 2005-07-21 | 2012-07-25 | ソニー株式会社 | 物理情報取得方法および物理情報取得装置 |
BRPI0615958B8 (pt) | 2005-07-28 | 2021-05-25 | Id Fish Tech Inc | composição para aumentar a permeabilidade de paredes celulares e membranas celulares de mycobacterium sp. e método para detectar um alvo em uma célula |
FR2889293B1 (fr) | 2005-07-29 | 2009-12-18 | Burner Systems Int Bsi | Bruleur a gaz a multiples couronnes de flammes concentriques |
DE102005039091A1 (de) | 2005-08-06 | 2007-02-08 | Behr Gmbh & Co. Kg | Montageträgersystem |
JP5523705B2 (ja) | 2005-08-29 | 2014-06-18 | レグルス・セラピューティクス・インコーポレイテッド | Mir−122aをモジュレートする使用方法 |
WO2007028065A2 (en) | 2005-08-30 | 2007-03-08 | Isis Pharmaceuticals, Inc. | Chimeric oligomeric compounds for modulation of splicing |
US20090156088A1 (en) | 2005-09-09 | 2009-06-18 | Nikko Co., Ltd. | Ambience creation device, traveling toy, ambience creation method, and ambience creation program |
US20070077993A1 (en) | 2005-09-30 | 2007-04-05 | Midgley Timothy M | Method and apparatus for collecting user game play data and crediting users in a gaming environment |
EP2341059A1 (en) * | 2005-10-12 | 2011-07-06 | Idera Pharmaceuticals, Inc. | Immune regulatory oligonucleotide (IRO) compounds to modulate toll-like receptor based immune response |
US9308252B2 (en) * | 2005-10-27 | 2016-04-12 | Cook Biotech, Inc. | Extracellular matrix materials as vaccine adjuvants for diseases associated with infectious pathogens or toxins |
US7320965B2 (en) | 2005-10-28 | 2008-01-22 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of Huntingtin gene |
EP1942185A4 (en) | 2005-10-28 | 2009-11-25 | Tosoh Corp | PROCESS FOR PREPARING CAROTINOIDY SYNTHETIZING MICROORGANISM AND METHOD FOR CAROTINOID PRODUCTION |
WO2007059041A2 (en) | 2005-11-11 | 2007-05-24 | Pfizer, Inc. | Combinations and methods of using an immunomodulatory oligodeoxynucleotide |
WO2007064291A1 (en) | 2005-11-30 | 2007-06-07 | Jyoti Chattopadhyaya | Method and compounds for rna synthesis |
CA2632968A1 (en) | 2005-12-02 | 2007-06-07 | Isis Pharmaceuticals, Inc. | Antibacterial 4,5-substituted aminoglycoside analogs having multiple substituents |
US8076303B2 (en) | 2005-12-13 | 2011-12-13 | Spring Bank Pharmaceuticals, Inc. | Nucleotide and oligonucleotide prodrugs |
KR101029167B1 (ko) | 2005-12-21 | 2011-04-12 | 화이자 프로덕츠 인크. | 강력한 키나제 억제제인 카르보닐아미노 피롤로피라졸 |
US7951934B2 (en) | 2006-01-26 | 2011-05-31 | Isis Pharmaceuticals, Inc. | Compositions and their uses directed to huntingtin |
EP2314594B1 (en) | 2006-01-27 | 2014-07-23 | Isis Pharmaceuticals, Inc. | 6-modified bicyclic nucleic acid analogs |
EP1991678B2 (en) | 2006-02-15 | 2020-07-15 | Rechtsanwalt Thomas Beck | Compositions and methods for oligonucleotide formulations |
US8383660B2 (en) | 2006-03-10 | 2013-02-26 | Pfizer Inc. | Dibenzyl amine compounds and derivatives |
JP2009533022A (ja) | 2006-03-31 | 2009-09-17 | アプライド バイオシステムズ, エルエルシー | ローダミン標識されたオリゴヌクレオチドを合成するために有用な試薬 |
EP2010679A2 (en) | 2006-04-06 | 2009-01-07 | Ibis Biosciences, Inc. | Compositions for the use in identification of fungi |
ATE476424T1 (de) | 2006-04-20 | 2010-08-15 | Hoffmann La Roche | Diazepanderivate als modulatoren von chemokinrezeptoren |
CN101432440B (zh) | 2006-04-24 | 2013-08-21 | 西格马食品可变资本有限公司 | 通过实时聚合酶链反应检测和多重、同时量化病原体的方法 |
GB0608838D0 (en) | 2006-05-04 | 2006-06-14 | Novartis Ag | Organic compounds |
KR101441700B1 (ko) | 2006-05-05 | 2014-09-18 | 아이시스 파마수티컬즈 인코포레이티드 | Pcsk9 발현을 조절하는 화합물 및 방법 |
US8158598B2 (en) | 2006-05-05 | 2012-04-17 | Isis Pharmaceuticals, Inc. | Compositions and their uses directed to PTPR alpha |
US20090012120A1 (en) | 2006-05-10 | 2009-01-08 | Board Of Trustees Of Michigan State University | Synthesis of N-heterocycles, beta-amino acids, and allyl amines via aza-payne mediated reaction of ylides and hydroxy aziridines |
US7666854B2 (en) | 2006-05-11 | 2010-02-23 | Isis Pharmaceuticals, Inc. | Bis-modified bicyclic nucleic acid analogs |
ES2389737T3 (es) | 2006-05-11 | 2012-10-31 | Isis Pharmaceuticals, Inc. | Análogos de ácidos nucleicos bicíclicos modificados en 5' |
EP2046993A4 (en) | 2006-07-07 | 2010-11-17 | Univ Massachusetts | RNA INTERFERENCE COMPOSITIONS AND METHOD FOR TREATING MORBUS HUNTINGTON |
CN101506368B (zh) | 2006-07-12 | 2017-02-08 | 加利福尼亚大学董事会 | 通过可逆的磷酸三酯电荷中和保护基转导运输核酸 |
EP2051977A2 (en) | 2006-07-20 | 2009-04-29 | Amgen Inc. | SUBSTITUTED AZOLE AROMATIC HETEROCYCLES AS INHIBITORS OF LLbeta-HSD-1 |
US8101585B2 (en) | 2006-08-04 | 2012-01-24 | Isis Pharmaceuticals, Inc. | Compositions and methods for the modulation of JNK proteins |
AT504194B1 (de) | 2006-09-07 | 2008-07-15 | Oesterr Rotes Kreuz | Bakteriennachweis |
US8138330B2 (en) | 2006-09-11 | 2012-03-20 | Sigma-Aldrich Co. Llc | Process for the synthesis of oligonucleotides |
CN101517082B (zh) | 2006-09-27 | 2014-01-22 | 科勒制药有限责任公司 | 具有增强的免疫刺激活性的含疏水性T类似物的CpG寡聚核苷酸类似物 |
JP5665317B2 (ja) | 2006-10-18 | 2015-02-04 | アイシス ファーマシューティカルズ, インコーポレーテッド | アンチセンス化合物 |
RU2009115687A (ru) | 2006-10-26 | 2010-11-10 | Коли Фармасьютикал Гмбх (De) | Олигорибонуклеотиды и их применения |
FR2908414B1 (fr) | 2006-11-13 | 2012-01-20 | Centre Nat Rech Scient | Immobilisation de proteines membranaires sur un support par l'intermediaire d'une molecule amphiphile |
JP2010510224A (ja) | 2006-11-17 | 2010-04-02 | アボット・ラボラトリーズ | ケモカイン受容体拮抗薬としてのアミノピロリジン類 |
MX2009005527A (es) | 2006-11-27 | 2009-06-08 | Isis Pharmaceuticals Inc | Metodos para el tratamiento de hipercolesterolemia. |
US8093222B2 (en) | 2006-11-27 | 2012-01-10 | Isis Pharmaceuticals, Inc. | Methods for treating hypercholesterolemia |
UY30892A1 (es) | 2007-02-07 | 2008-09-02 | Smithkline Beckman Corp | Inhibidores de la actividad akt |
JP2010522245A (ja) | 2007-03-24 | 2010-07-01 | ゲンザイム コーポレイション | ヒトアポリポタンパク質bと相補的なアンチセンスオリゴヌクレオチドの投与 |
US7943591B2 (en) | 2007-05-11 | 2011-05-17 | Adynxx, Inc. | Gene expression and pain |
WO2008143343A1 (ja) | 2007-05-24 | 2008-11-27 | Kyorin Pharmaceutical Co., Ltd. | 14位置換基に複素芳香環カルボン酸構造を有するムチリン誘導体 |
GB0710186D0 (en) | 2007-05-29 | 2007-07-04 | Texas Instr Denmark | PWM loop with minimum allasing error property |
AU2008260277C1 (en) | 2007-05-30 | 2014-04-17 | Isis Pharmaceuticals, Inc. | N-substituted-aminomethylene bridged bicyclic nucleic acid analogs |
MX2009012787A (es) | 2007-06-05 | 2009-12-15 | Nsab Af Neurosearch Sweden Ab | Nuevas fenilpirrolidinas disustituidas como moduladores de neurotransmision catecolaminergica cortical. |
US8278426B2 (en) | 2007-06-08 | 2012-10-02 | Isis Pharmaceuticals, Inc. | Carbocyclic bicyclic nucleic acid analogs |
EP2164865A2 (en) | 2007-06-13 | 2010-03-24 | Hochschule Mannheim | Compounds for the modulation of huntingtin aggregation, methods and means for identifying such compounds |
ATE462787T1 (de) | 2007-06-18 | 2010-04-15 | Commissariat Energie Atomique | Reversibles sirna-silencing eines mutierten und endogenen huntington-wildtypgens und dessen anwendung zur behandlung von morbus huntington |
WO2009006478A2 (en) | 2007-07-05 | 2009-01-08 | Isis Pharmaceuticals, Inc. | 6-disubstituted bicyclic nucleic acid analogs |
CA2692161C (en) * | 2007-07-09 | 2015-09-29 | Idera Pharmaceuticals, Inc. | Stabilized immune modulatory rna (simra) compounds |
AU2008281281A1 (en) | 2007-07-31 | 2009-02-05 | University Of Saskatchewan | Genetic variation in Pro-Melanin-Concentrating Hormone gene affects carcass traits in cattle |
WO2009017803A2 (en) | 2007-08-02 | 2009-02-05 | The Texas A & M University System | Antisense microrna and uses therefor |
US8853375B2 (en) * | 2007-08-15 | 2014-10-07 | Idera Pharmaceuticals, Inc. | Toll like receptor modulators |
JP5792955B2 (ja) | 2007-10-01 | 2015-10-14 | アイシス ファーマシューティカルズ, インコーポレーテッド | 線維芽細胞増殖因子受容体4発現のアンチセンスモジュレーション |
ES2336873B1 (es) | 2007-11-07 | 2011-01-24 | Proyecto De Biomedicina Cima, S.L. | Composicion farmaceutica para el tratamiento de cancer. |
KR100886139B1 (ko) | 2007-11-13 | 2009-02-27 | 주식회사 삼천리제약 | 올리고뉴클레오타이드의 제조방법 |
TW200930375A (en) | 2007-12-21 | 2009-07-16 | Exelixis Inc | Benzofuropyrimidinones |
TWI340765B (en) | 2007-12-26 | 2011-04-21 | Ind Tech Res Inst | Oligonucleotide sequences and dna chip for identifying filamentous microorganisms and the identification method thereof |
US20100309376A1 (en) | 2008-01-15 | 2010-12-09 | Yungchun Lei | Multimedia Presenting System, Multimedia Processing Apparatus Thereof, and Method for Presenting Video and Audio Signals |
WO2009098197A1 (en) | 2008-02-04 | 2009-08-13 | Biofocus Dpi B.V. | Target sequences and methods to identify the same, useful in treatment of neurodegenerative diseases |
JP2009190983A (ja) | 2008-02-12 | 2009-08-27 | Tokyo Institute Of Technology | オリゴヌクレオチド誘導体 |
EP2282744B1 (en) | 2008-03-21 | 2018-01-17 | Ionis Pharmaceuticals, Inc. | Oligomeric compounds comprising tricyclic nucleosides and methods for their use |
EP2271351A4 (en) | 2008-04-03 | 2016-08-31 | Spring Bank Pharmaceuticals Inc | COMPOSITIONS AND METHODS FOR TREATING VIRAL INFECTIONS |
US9290534B2 (en) | 2008-04-04 | 2016-03-22 | Ionis Pharmaceuticals, Inc. | Oligomeric compounds having at least one neutrally linked terminal bicyclic nucleoside |
AU2009244013B2 (en) | 2008-05-09 | 2015-06-25 | The University Of British Columbia | Methods and compositions for the treatment of Huntington's disease |
US8679750B2 (en) | 2008-05-09 | 2014-03-25 | The University Of British Columbia | Methods and compositions for the treatment of Huntington'S disease |
WO2009143391A2 (en) | 2008-05-22 | 2009-11-26 | Isis Pharmaceuticals, Inc | Methods for modulation expression of creb |
WO2009143387A2 (en) | 2008-05-22 | 2009-11-26 | Isis Pharmaceuticals, Inc. | Modulation of smrt expression |
US8541388B2 (en) | 2008-05-22 | 2013-09-24 | Isis Pharmaceuticals, Inc. | Methods for modulating expression of RBP4 |
WO2009148605A2 (en) | 2008-06-04 | 2009-12-10 | Isis Pharmaceuticals, Inc. | Methods for treating hypercholesterolemia |
EP2320895A2 (en) | 2008-07-03 | 2011-05-18 | Exelixis, Inc. | Cdk modulators |
US20100064146A1 (en) | 2008-09-08 | 2010-03-11 | Integral Wave Technologies, Inc. | Power system design tool |
EP2346883B1 (en) | 2008-09-23 | 2016-03-23 | Scott G. Petersen | Self delivering bio-labile phosphate protected pro-oligos for oligonucleotide based therapeutics and mediating rna interference |
WO2010036696A1 (en) | 2008-09-24 | 2010-04-01 | Isis Pharmaceuticals, Inc. | Cyclohexenyl nucleic acid analogs |
US8501805B2 (en) | 2008-09-24 | 2013-08-06 | Isis Pharmaceuticals, Inc. | Substituted alpha-L-bicyclic nucleosides |
EP2344204A4 (en) | 2008-10-07 | 2012-07-04 | Harvard College | TELOMERASE INHIBITOR AND METHOD OF USE THEREOF |
NZ591391A (en) | 2008-10-22 | 2012-10-26 | Quark Pharmaceuticals Inc | Non-invasive methods for treating eye disorders using a topical oligonucleotide composition |
CA2741294C (en) | 2008-10-24 | 2018-04-24 | Isis Pharmaceuticals, Inc. | 5' and 2' bis-substituted nucleosides and oligomeric compounds prepared therefrom |
BRPI0923225A2 (pt) | 2008-12-02 | 2016-10-04 | Chiralgen Ltd | metodo para sintese de acidos nucleicos modificados no atomo de fosforo |
JP2012513450A (ja) | 2008-12-23 | 2012-06-14 | ギリンダス・アメリカ・インコーポレイテッド | 硫化剤およびオリゴヌクレオチドを合成するためのその使用 |
WO2010080953A1 (en) | 2009-01-08 | 2010-07-15 | Isis Pharmaceuticals, Inc. | Transgenic murine model of human lipoprotein metabolism, hypercholesterolemia and cardiovascular disease |
WO2010091301A1 (en) | 2009-02-06 | 2010-08-12 | Isis Pharmaceuticals, Inc. | Oligomeric compounds and excipients |
WO2010093705A2 (en) * | 2009-02-10 | 2010-08-19 | Idera Pharmaceuticals, Inc. | Synthetic rna-based agonists of tlr7 |
EP3424939A1 (en) | 2009-03-02 | 2019-01-09 | Alnylam Pharmaceuticals Inc. | Nucleic acid chemical modifications |
WO2010107838A1 (en) | 2009-03-16 | 2010-09-23 | Isis Pharmaceuticals, Inc. | Targeting apolipoprotein b for the reduction of apolipoprotein c-iii |
US8987222B2 (en) | 2009-04-08 | 2015-03-24 | University Of Massachusetts | Single nucleotide polymorphism (SNP) targeting therapies for the treatment of huntington'S disease |
US9260493B2 (en) | 2009-05-07 | 2016-02-16 | The Regents Of The University Of California | Transducible delivery of nucleic acids using modified dsRNA binding domains |
KR20120052909A (ko) | 2009-06-01 | 2012-05-24 | 더 리전트 오브 더 유니버시티 오브 캘리포니아 | 핵산 수송용 조성물 및 이의 사용 방법 |
CA2764374C (en) * | 2009-06-05 | 2019-11-19 | Infectious Disease Research Institute | Synthetic glucopyranosyl lipid adjuvants |
CA2767253A1 (en) | 2009-07-06 | 2011-01-13 | Ontorii, Inc. | Novel nucleic acid prodrugs and methods of use thereof |
WO2011005942A2 (en) * | 2009-07-08 | 2011-01-13 | Idera Pharmaceuticals, Inc. | Oligonucleotide-based compounds as inhibitors of toll-like receptors |
WO2011015573A1 (en) | 2009-08-03 | 2011-02-10 | Galapagos Nv | Molecular targets and compounds, and methods to identify the same, useful in the treatment of neurodegenerative diseases |
WO2011015572A1 (en) | 2009-08-03 | 2011-02-10 | Galapagos Nv | Molecular targets and compounds, and methods to identify the same, useful in the treatment of neurodegenerative diseases |
EP2462153B1 (en) | 2009-08-06 | 2015-07-29 | Isis Pharmaceuticals, Inc. | Bicyclic cyclohexose nucleic acid analogs |
CN111705058A (zh) | 2009-09-11 | 2020-09-25 | Ionis制药公司 | 亨廷顿表达的调节 |
EP2479182B8 (en) | 2009-09-16 | 2016-07-13 | Wave Life Sciences Japan, Inc. | Novel protecting group for synthesizing rna and derivative thereof |
EP2480667A4 (en) | 2009-09-25 | 2013-07-03 | Isis Pharmaceuticals Inc | MODULATION OF TTC39 EXPRESSION FOR HDL INCREASE |
EP2488524B1 (en) | 2009-10-15 | 2013-07-03 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidine compounds |
EP2512246B1 (en) | 2009-12-17 | 2015-09-30 | Merck Sharp & Dohme Corp. | Aminopyrimidines as syk inhibitors |
CN102812361A (zh) | 2009-12-28 | 2012-12-05 | 阿茨拉实验室有限公司 | 诊断凝胶组合物、制造诊断凝胶组合物的方法 |
CN106146591B (zh) | 2010-01-08 | 2020-07-31 | Ionis制药公司 | 血管生成素样3表达的调节 |
US8750507B2 (en) | 2010-01-25 | 2014-06-10 | Cisco Technology, Inc. | Dynamic group creation for managed key servers |
AU2011213562B2 (en) | 2010-02-08 | 2016-07-07 | Ionis Pharmaceuticals, Inc. | Selective reduction of allelic variants |
JP6018506B2 (ja) | 2010-02-08 | 2016-11-02 | アイオーニス ファーマシューティカルズ, インコーポレーテッドIonis Pharmaceuticals,Inc. | 対立遺伝子多様体の選択的低減 |
MX2012009316A (es) * | 2010-02-10 | 2012-09-12 | Glaxosmithkline Llc | Maleato de 6-amino-2-{ [ (1s) -1-metil-butil] -oxi} -9-[ 5-(1-piperidinil) -7, 9-dihidro-8h-purin-8-ona. |
US8859755B2 (en) | 2010-03-05 | 2014-10-14 | Chiralgen, Ltd. | Method for preparing ribonucleoside phosphorothioate |
WO2011127175A1 (en) | 2010-04-06 | 2011-10-13 | Isis Pharmaceuticals, Inc. | Modulation of cd130 (gp130) expression |
CN102844434A (zh) | 2010-04-07 | 2012-12-26 | Isis制药公司 | Cetp表达的调节 |
US8993738B2 (en) | 2010-04-28 | 2015-03-31 | Isis Pharmaceuticals, Inc. | Modified nucleosides, analogs thereof and oligomeric compounds prepared therefrom |
WO2011139911A2 (en) | 2010-04-29 | 2011-11-10 | Isis Pharmaceuticals, Inc. | Lipid formulated single stranded rna |
GB201008902D0 (en) | 2010-05-27 | 2010-07-14 | Imp Innovations Ltd | Membrane enhanced polymer sythesis |
CA2809439A1 (en) | 2010-08-31 | 2012-03-08 | Merck Sharp & Dohme Corp. | Novel single chemical entities and methods for delivery of oligonucleotides |
WO2012039448A1 (ja) | 2010-09-24 | 2012-03-29 | 株式会社キラルジェン | 不斉補助基 |
WO2012043633A1 (ja) | 2010-09-30 | 2012-04-05 | 独立行政法人国立精神・神経医療研究センター | 優性変異遺伝子発現抑制剤 |
KR101381048B1 (ko) | 2010-10-20 | 2014-04-14 | 씨제이제일제당 (주) | O-포스포세린 생산 균주 및 이로부터 생산된 o-포스포세린으로부터 l-시스테인 또는 이의 유도체의 생산방법 |
AU2011325956B2 (en) | 2010-11-12 | 2016-07-14 | The General Hospital Corporation | Polycomb-associated non-coding RNAs |
EP2647644B1 (en) | 2010-11-30 | 2020-09-09 | Wave Life Sciences Japan, Inc. | 2'-o-modified rna |
WO2012109667A1 (en) | 2011-02-12 | 2012-08-16 | University Of Iowa Research Foundation | Therapeutic compounds |
WO2012151324A1 (en) | 2011-05-02 | 2012-11-08 | Isis Pharmaceuticals, Inc. | Antisense compounds targeting genes associated with usher syndrome |
EP2734208B1 (en) | 2011-07-19 | 2017-03-01 | Wave Life Sciences Ltd. | Methods for the synthesis of functionalized nucleic acids |
WO2013022990A1 (en) | 2011-08-11 | 2013-02-14 | Isis Pharmaceuticals, Inc. | Selective antisense compounds and uses thereof |
WO2013134558A1 (en) | 2012-03-07 | 2013-09-12 | The Texas A & M University System | Cancer treatment targeting non-coding rna overexpression |
DK2857412T3 (en) | 2012-05-30 | 2017-04-03 | Hokkaido System Science Co Ltd | Method for Oligonucleotide Synthesis Using High-Resolution Liquid Phase Carrier |
CA2879066C (en) * | 2012-07-13 | 2019-08-13 | Shin Nippon Biomedical Laboratories, Ltd. | Chiral nucleic acid adjuvant |
KR20220139425A (ko) | 2012-07-13 | 2022-10-14 | 웨이브 라이프 사이언시스 리미티드 | 키랄 제어 |
WO2014010250A1 (en) | 2012-07-13 | 2014-01-16 | Chiralgen, Ltd. | Asymmetric auxiliary group |
CA2879693A1 (en) | 2012-08-06 | 2014-02-13 | Alnylam Pharmaceuticals, Inc. | Carbohydrate conjugated rna agents and process for their preparation |
EP3459549B1 (en) | 2012-10-12 | 2022-04-06 | Ionis Pharmaceuticals, Inc. | Selective antisense compounds and uses thereof |
CR20190269A (es) | 2013-05-01 | 2019-09-13 | Ionis Pharmaceuticals Inc | COMPOSICIONES Y MÉTODOS PARA MODULAR LA EXPRESIÓN DE TTR Y VHB (Divisonal 2015-0612) |
TWI772856B (zh) | 2013-07-19 | 2022-08-01 | 美商百健Ma公司 | 用於調節τ蛋白表現之組合物 |
US10894963B2 (en) * | 2013-07-25 | 2021-01-19 | Exicure, Inc. | Spherical nucleic acid-based constructs as immunostimulatory agents for prophylactic and therapeutic use |
BR112016007255A2 (pt) | 2013-10-03 | 2017-09-12 | Moderna Therapeutics Inc | polinucleotídeos que codificam receptor de lipoproteína de baixa densidade |
WO2015051366A2 (en) | 2013-10-04 | 2015-04-09 | Novartis Ag | Novel formats for organic compounds for use in rna interference |
NZ719477A (en) | 2013-11-11 | 2022-05-27 | Sangamo Therapeutics Inc | Methods and compositions for treating huntington’s disease |
EP2918275B1 (en) | 2013-12-13 | 2016-05-18 | Moderna Therapeutics, Inc. | Alternative nucleic acid molecules and uses thereof |
WO2015108046A1 (ja) * | 2014-01-15 | 2015-07-23 | 株式会社新日本科学 | 抗アレルギー作用を有するキラル核酸アジュバンド及び抗アレルギー剤 |
EP3095459A4 (en) * | 2014-01-15 | 2017-08-23 | Shin Nippon Biomedical Laboratories, Ltd. | Chiral nucleic acid adjuvant having antitumor effect and antitumor agent |
EP3095461A4 (en) * | 2014-01-15 | 2017-08-23 | Shin Nippon Biomedical Laboratories, Ltd. | Chiral nucleic acid adjuvant having immunity induction activity, and immunity induction activator |
MY193116A (en) | 2014-01-16 | 2022-09-26 | Wave Life Sciences Ltd | Chiral design |
WO2015171932A1 (en) | 2014-05-08 | 2015-11-12 | Sangamo Biosciences, Inc. | Methods and compositions for treating huntington's disease |
EP3146051B8 (en) | 2014-05-20 | 2019-11-27 | University of Iowa Research Foundation | Huntington's disease therapeutic compounds |
US20160017327A1 (en) | 2014-07-11 | 2016-01-21 | The Johns Hopkins University | Phosphorodiamidate morpholino oligomers (pmos) and their use in suppression of mutant huntingtin expression and attenuation of neurotoxicity |
EP3169693B1 (en) | 2014-07-16 | 2022-03-09 | ModernaTX, Inc. | Chimeric polynucleotides |
EP2982758A1 (en) | 2014-08-04 | 2016-02-10 | Centre Hospitalier Universitaire Vaudois (CHUV) | Genome editing for the treatment of huntington's disease |
WO2016037191A1 (en) | 2014-09-05 | 2016-03-10 | Health Research, Inc. | Use of huntingtin-derived plasmids and peptides for active immunization as a huntington's disease (hd) therapeutic |
EP3220921A1 (en) | 2014-11-19 | 2017-09-27 | Roche Innovation Center Copenhagen A/S | Lna chiral phosphorothioates |
EP3237618B1 (en) | 2014-12-24 | 2019-05-22 | uniQure IP B.V. | Rnai induced huntingtin gene suppression |
MY181458A (en) | 2015-02-10 | 2020-12-22 | Genzyme Corp | Variant rnai |
EP3277814B1 (en) | 2015-04-03 | 2020-06-03 | University of Massachusetts | Oligonucleotide compounds for targeting huntingtin mrna |
EP3183347A4 (en) | 2015-10-17 | 2018-04-18 | Lifesplice Pharma LLC | Splice modulating oligonucleotides and methods of use thereof |
-
2013
- 2013-07-12 CA CA2879066A patent/CA2879066C/en active Active
- 2013-07-12 MX MX2015000497A patent/MX356830B/es active IP Right Grant
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- 2013-07-12 RU RU2015100198A patent/RU2677639C2/ru active
- 2013-07-12 EP EP13816791.1A patent/EP2873674B1/en active Active
- 2013-07-12 WO PCT/JP2013/069107 patent/WO2014010718A1/ja active Application Filing
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- 2013-07-12 SG SG11201500243WA patent/SG11201500243WA/en unknown
-
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- 2015-01-12 IL IL236685A patent/IL236685B/en active IP Right Grant
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001503267A (ja) * | 1996-10-30 | 2001-03-13 | ユニバーシティ オブ アイオワ リサーチ ファウンデーション | 免疫刺激性核酸分子 |
WO2000006588A1 (en) * | 1998-07-27 | 2000-02-10 | University Of Iowa Research Foundation | STEREOISOMERS OF CpG OLIGONUCLEOTIDES AND RELATED METHODS |
WO2001022990A2 (en) * | 1999-09-27 | 2001-04-05 | Coley Pharmaceutical Group, Inc. | Methods related to immunostimulatory nucleic acid-induced interferon |
CN1688192A (zh) * | 2002-08-19 | 2005-10-26 | 科勒制药集团有限公司 | 免疫刺激核酸 |
JP2006515277A (ja) * | 2002-10-29 | 2006-05-25 | コーリー ファーマシューティカル グループ, リミテッド | C型肝炎ウィルス感染の処置および予防に関する方法および製品 |
JP2008531018A (ja) * | 2005-02-24 | 2008-08-14 | コーリー ファーマシューティカル グループ,インコーポレイテッド | 免疫刺激性オリゴヌクレオチド |
WO2007139190A1 (ja) * | 2006-05-31 | 2007-12-06 | Toray Industries, Inc. | 免疫刺激オリゴヌクレオチド及びその医薬用途 |
Non-Patent Citations (3)
Title |
---|
ARTHUR M. KRIEG,等: "P-Chirality-Dependent Immune Activation by Phosphorothioate CpG Oligodeoxynucleotides", 《OLIGONUCLEOTIDES》 * |
DONG YU,等: "Stereo-Enriched Phosphorothioate Oligodeoxynucleotides: Synthesis, Biophysical and Biological Properties", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
DONGBUM KIM,等: ""Immunostimulation and anti-DNA antibody production by backbone modified CpG-DNA"", 《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106256905A (zh) * | 2015-11-24 | 2016-12-28 | 华中农业大学 | 一种对草鱼有免疫增强活性的CpG ODN序列及其应用 |
CN106256905B (zh) * | 2015-11-24 | 2019-08-13 | 华中农业大学 | 一种对草鱼有免疫增强活性的CpG ODN序列及其应用 |
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JP6246121B2 (ja) | 2017-12-13 |
CN104684923B (zh) | 2018-09-28 |
JPWO2014010718A1 (ja) | 2016-06-23 |
MX356830B (es) | 2018-06-15 |
CA2879066C (en) | 2019-08-13 |
RU2015100198A (ru) | 2016-08-27 |
RU2677639C2 (ru) | 2019-01-18 |
KR20150028352A (ko) | 2015-03-13 |
EP2873674B1 (en) | 2020-05-06 |
MX2015000497A (es) | 2015-06-05 |
US9617547B2 (en) | 2017-04-11 |
IL236685B (en) | 2019-05-30 |
AU2013287630B2 (en) | 2017-05-25 |
EP2873674A1 (en) | 2015-05-20 |
SG11201500243WA (en) | 2015-04-29 |
US20150166999A1 (en) | 2015-06-18 |
WO2014010718A1 (ja) | 2014-01-16 |
BR112015000723A2 (pt) | 2017-06-27 |
CA2879066A1 (en) | 2014-01-16 |
KR101835401B1 (ko) | 2018-03-08 |
IL236685A0 (en) | 2015-02-26 |
EP2873674A4 (en) | 2016-04-20 |
AU2013287630A1 (en) | 2015-02-05 |
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