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    DELIVERY OF RNAI CONSTRUCTS TO OLIGODENDROCYTES
    64.
    发明申请
    DELIVERY OF RNAI CONSTRUCTS TO OLIGODENDROCYTES 审中-公开
    将RNAI结构递送到寡糖脱乙酰壳多糖

    公开(公告)号：US20110118340A1

    公开(公告)日：2011-05-19

    申请号：US12866444

    申请日：2009-02-06

    申请人： Muthiah Manoharan ,  Kallanthottathil G. Rajeev ,  Dinah Sah ,  William Querbes ,  Pamela Tan ,  Qingmin Chen

    发明人： Muthiah Manoharan ,  Kallanthottathil G. Rajeev ,  Dinah Sah ,  William Querbes ,  Pamela Tan ,  Qingmin Chen

    IPC分类号： A61K31/7088 ,  A61P31/12 ,  A61P25/00 ,  A61P25/18 ,  A61P25/16 ,  A61P25/28

    CPC分类号： C12N15/1131 ,  A61K47/551 ,  A61K47/554 ,  C12N15/111 ,  C12N2310/14 ,  C12N2310/315 ,  C12N2310/321 ,  C12N2310/3515 ,  C12N2320/11 ,  C12N2320/32 ,  C12N2310/3521

    摘要： The invention provides methods for delivering a double-stranded nbonucleic acid (dsRNA) to the central nervous system of a subject, and particularly, to oligodendrocytes of a subject by localized delivery to the brain, e.g., to the corpus caïlosum. For example, the dsRNA molecules can include a first sequence that is selected from the Sroup consisting of the sense sequences of Tables 8, 10, 13-16, and a second sequence selected from the group consisting of the antisense sequences of Tables 8, 10, and 13-16. The dsRNA molecules can include naturally occurring nucleotides or can include at least one modified nucleotide, such as a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, or a terminal nucleotide linked to a conjugate group, such as to a cholesteryl derivative or a vitamin E group. Alternatively, the modified nucleotide may be chosen from the group consisting of a 2f-deoxy-2′-fliιioro modified nucleotide, a 2′-de-oxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, a phosphoramidate, and a non-natural bas comprising nucleotide. Generally, such modified sequences will be based on a first sequence of a dsRNA selected from the group consisting of the sense sequences of Tables 8, 10, and 13-16, and a second sequence selected from the group consisting of the antisense sequences of Tables 8 10, and 13-16.

    摘要翻译： 本发明提供了将双链核糖核酸（dsRNA）递送到受试者的中枢神经系统，特别是通过局部递送至脑的例如对胼the体的受试者的少突胶质细胞的方法。 例如，dsRNA分子可以包括选自由表8,10,13-16的有义序列组成的组的第一序列和选自表8,10的反义序列的第二序列 ，和13-16。 dsRNA分子可以包括天然存在的核苷酸，或者可以包括至少一个修饰的核苷酸，例如2'-O-甲基修饰的核苷酸，包含5'-硫代磷酸酯基团的核苷酸或与缀合物连接的末端核苷酸， 关于胆固醇衍生物或维生素E组。 或者，修饰的核苷酸可以选自2f-脱氧-2'-氟修饰的核苷酸，2'-脱氧修饰的核苷酸，锁定的核苷酸，无碱基的核苷酸，2'-氨基修饰的 核苷酸，2'-烷基修饰的核苷酸，吗啉代核苷酸，氨基磷酸酯和包含核苷酸的非天然碱基。 通常，这样的修饰序列将基于选自表8,10和13-16的有义序列的dsRNA的第一序列和选自下表的反义序列的第二序列 8 10和13-16。

    Oligonucleotides comprising a ligand tethered to a modified or non-natural nucleobase
    65.
    发明授权
    Oligonucleotides comprising a ligand tethered to a modified or non-natural nucleobase 有权
    包含与修饰或非天然核碱基连接的配体的寡核苷酸

    公开(公告)号：US07632932B2

    公开(公告)日：2009-12-15

    申请号：US11197753

    申请日：2005-08-04

    申请人： Muthiah Manoharan ,  Kallanthottathil G. Rajeev ,  Jie Xia

    发明人： Muthiah Manoharan ,  Kallanthottathil G. Rajeev ,  Jie Xia

    IPC分类号： C07H21/00 ,  C07H21/02 ,  C07H21/04 ,  C12Q1/68

    CPC分类号： C07H21/00 ,  A61K31/7115 ,  C07F9/6561 ,  C07H21/02 ,  C12Q1/6883 ,  Y02A50/385 ,  Y02A50/387 ,  Y02A50/393 ,  Y02A50/395 ,  Y02A50/411 ,  Y02A50/463 ,  Y02A50/465 ,  Y02A50/467

    摘要： One aspect of the present invention relates to a double-stranded oligonucleotide comprising at least one ligand tethered to an altered or non-natural nucleobase. In certain embodiments, the non-natural nucleobase is difluorotolyl, nitropyrrolyl, or nitroimidazolyl. In certain embodiments, the ligand is a steroid or aromatic compound. In certain embodiments, only one of the two oligonucleotide strands comprising the double-stranded oligonucleotide contains a ligand tethered to an altered or non-natural nucleobase. In certain embodiments, both of the oligonucleotide strands comprising the double-stranded oligonucleotide independently contain a ligand tethered to an altered or non-natural nucleobase. In certain embodiments, the oligonucleotide strands comprise at least one modified sugar moiety. Another aspect of the present invention relates to a single-stranded oligonucleotide comprising at least one ligand tethered to an altered or non-natural nucleobase. In certain embodiments, the non-natural nucleobase is difluorotolyl, nitropyrrolyl, or nitroimidazolyl. In certain embodiments, the ligand is a steroid or aromatic compound. In certain embodiments, the ribose sugar moiety that occurs naturally in nucleosides is replaced with a hexose sugar, polycyclic heteroalkyl ring, or cyclohexenyl group. In certain embodiments, at least one phosphate linkage in the oligonucleotide has been replaced with a phosphorothioate linkage.

    摘要翻译： 本发明的一个方面涉及包含至少一个与改变的或非天然核碱基连接的配体的双链寡核苷酸。 在某些实施方案中，非天然核碱基是二氟苯甲酰基，硝基吡咯基或硝基咪唑基。 在某些实施方案中，配体是类固醇或芳族化合物。 在某些实施方案中，包含双链寡核苷酸的两条寡核苷酸链中只有一条含有与改变的或非天然核碱基连接的配体。 在某些实施方案中，包含双链寡核苷酸的两条寡核苷酸链都独立地包含与改变的或非天然核碱基连接的配体。 在某些实施方案中，寡核苷酸链包含至少一个修饰的糖部分。 本发明的另一方面涉及包含至少一个与改变的或非天然核碱基连接的配体的单链寡核苷酸。 在某些实施方案中，非天然核碱基是二氟苯甲酰基，硝基吡咯基或硝基咪唑基。 在某些实施方案中，配体是类固醇或芳族化合物。 在某些实施方案中，在核苷中天然存在的核糖部分被己糖，多环杂烷基环或环己烯基取代。 在某些实施方案中，寡核苷酸中的至少一个磷酸键被硫代磷酸酯键取代。

    iRNA agents with biocleavable tethers
    68.
    发明授权
    iRNA agents with biocleavable tethers 有权
    具有生物可清除系绳的iRNA试剂

    公开(公告)号：US08426377B2

    公开(公告)日：2013-04-23

    申请号：US12724267

    申请日：2010-03-15

    申请人： Muthiah Manoharan ,  Kallanthottathil G. Rajeev

    发明人： Muthiah Manoharan ,  Kallanthottathil G. Rajeev

    IPC分类号： A61K31/70 ,  C07H21/04 ,  C07H5/06

    CPC分类号： C12N15/113 ,  C12N15/111 ,  C12N2310/14 ,  C12N2310/323 ,  C12N2310/3511 ,  C12N2320/51

    摘要： The invention relates to iRNA agents, which preferably include a monomer in which the ribose moiety has been replaced by a moiety other than ribose that further includes a tether having one or more linking groups, in which at least one of the linking groups is a cleavable linking group. The tether in turn can be connected to a selected moiety, e.g., a ligand, e.g., a targeting or delivery moiety, or a moiety which alters a physical property. The cleavable linking group is one which is sufficiently stable outside the cell such that it allows targeting of a therapeutically beneficial amount of an iRNA agent (e.g., a single stranded or double stranded iRNA agent), coupled by way of the cleavable linking group to a targeting agent—to targets cells, but which upon entry into a target cell is cleaved to release the iRNA agent from the targeting agent.

    摘要翻译： 本发明涉及iRNA试剂，其优选包括其中核糖部分已被核糖替代的单体，其进一步包括具有一个或多个连接基团的系链，其中至少一个连接基团是可切割的 连接组。 系链又可以连接到所选择的部分，例如配体，例如靶向或递送部分，或改变物理性质的部分。 可切割连接基团是在细胞外部足够稳定的连接基团，使得其允许靶向治疗有益量的iRNA试剂（例如，单链或双链iRNA试剂），其通过可切割连接基团连接至 靶向细胞靶向细胞，但是在进入靶细胞时被切割以从靶向剂释放iRNA试剂。

    Oligonucleotides comprising a non-phosphate backbone linkage
    70.
    发明授权
    Oligonucleotides comprising a non-phosphate backbone linkage 有权
    包含非磷酸骨架键的寡核苷酸

    公开(公告)号：US08013136B2

    公开(公告)日：2011-09-06

    申请号：US12496268

    申请日：2009-07-01

    申请人： Muthiah Manoharan ,  Kallanthottathil G. Rajeev

    发明人： Muthiah Manoharan ,  Kallanthottathil G. Rajeev

    IPC分类号： C07H21/02 ,  C07H21/04

    CPC分类号： C12N15/111 ,  C07H19/04 ,  C07H19/12 ,  C07H19/16 ,  C07H19/167 ,  C07H19/173 ,  C07H21/02 ,  C12N15/1136 ,  C12N15/1137 ,  C12N2310/14 ,  C12N2310/312 ,  C12N2320/51

    摘要： One aspect of the present invention relates to a ribonucleoside substituted with a phosphonamidite group at the 3′-position. In certain embodiments, the phosphonamidite is an alkyl phosphonamidite. Another aspect of the present invention relates to a double-stranded oligonucleotide comprising at least one non-phosphate linkage. Representative non-phosphate linkages include phosphonate, hydroxylamine, hydroxylhydrazinyl, amide, and carbamate linkages. In certain embodiments, the non-phosphate linkage is a phosphonate linkage. In certain embodiments, a non-phosphate linkage occurs in only one strand. In certain embodiments, a non-phosphate linkage occurs in both strands. In certain embodiments, a ligand is bound to one of the oligonucleotide strands comprising the double-stranded oligonucleotide. In certain embodiments, a ligand is bound to both of the oligonucleotide strands comprising the double-stranded oligonucleotide. In certain embodiments, the oligonucleotide strands comprise at least one modified sugar moiety. Another aspect of the present invention relates to a single-stranded oligonucleotide comprising at least one non-phosphate linkage. Representative non-phosphate linkages include phosphonate, hydroxylamine, hydroxylhydrazinyl, amide, and carbamate linkages. In certain embodiments, the non-phosphate linkage is a phosphonate linkage. In certain embodiments, a ligand is bound to the oligonucleotide strand. In certain embodiments, the oligonucleotide comprises at least one modified sugar moiety.

    摘要翻译： 本发明的一个方面涉及在3'-位被亚磷酰胺基取代的核糖核苷。 在某些实施方案中，亚磷酰胺是烷基亚磷酰胺。 本发明的另一方面涉及包含至少一种非磷酸键的双链寡核苷酸。 代表性的非磷酸酯键包括膦酸酯，羟胺，羟基肼基，酰胺和氨基甲酸酯键。 在某些实施方案中，非磷酸酯键是膦酸酯键。 在某些实施方案中，非磷酸酯键仅出现在一条链中。 在某些实施方案中，在两条链中都发生非磷酸连接。 在某些实施方案中，配体与包含双链寡核苷酸的寡核苷酸链之一结合。 在某些实施方案中，配体与包含双链寡核苷酸的两条寡核苷酸链结合。 在某些实施方案中，寡核苷酸链包含至少一个修饰的糖部分。 本发明的另一方面涉及包含至少一种非磷酸键的单链寡核苷酸。 代表性的非磷酸酯键包括膦酸酯，羟胺，羟基肼基，酰胺和氨基甲酸酯键。 在某些实施方案中，非磷酸酯键是膦酸酯键。 在某些实施方案中，配体与寡核苷酸链结合。 在某些实施方案中，寡核苷酸包含至少一个修饰的糖部分。