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    Oligonucleotide Compositions and Methods of Making the Same
    101.
    发明申请
    Oligonucleotide Compositions and Methods of Making the Same 有权
    寡核苷酸组合物及其制备方法

    公开(公告)号：US20150337314A1

    公开(公告)日：2015-11-26

    申请号：US14699902

    申请日：2015-04-29

    申请人： GERON CORPORATION

    发明人： Premchandran H. Ramiya

    IPC分类号： C12N15/113 ,  C07H21/00

    CPC分类号： C07H21/00 ,  C12N15/113 ,  C12N15/1137 ,  C12N2310/113 ,  C12N2310/3145 ,  C12N2310/315 ,  C12N2310/3515 ,  C12P19/34 ,  C12Y207/07049

    摘要： The present disclosure provides a solid phase method of making oligonucleotides via sequential coupling cycles including at least one coupling of a dinucleotide dimer subunit to a free 3′-terminal group of a growing chain. The oligonucleotides include at least two nucleoside subunits joined by a N3′→P5′ phosphoramidate linkage. The method may include the steps of (a) deprotecting the protected 3′ amino group of a terminal nucleoside attached to a solid phase support, said deprotecting forming a free 3′ amino group; (b) contacting the free 3′ amino group with a 3′-protected amino-dinucleotide-5′-phosphoramidite dimer in the presence of a nucleophilic catalyst to form an internucleoside N3′→P5′ phosphoramidite linkage; and (c) oxidizing (e.g., sulfurizing) the linkage. The compositions produced by the subject methods may include a reduced amount of one or more (N−x) oligonucleotide products. Also provided are pharmaceutical compositions including the subject oligonucleotide compositions.

    摘要翻译： 本公开提供了通过连续偶联循环制备寡核苷酸的固相方法，其包括二核苷酸二聚体亚基与生长链的游离3'-端基的至少一个偶联。 寡核苷酸包括通过N 3'→P 5'氨基磷酸酯键连接的至少两个核苷亚基。 该方法可以包括以下步骤：（a）将连接于固相载体上的末端核苷的被保护的3'氨基脱保护，所述去保护形成游离的3'氨基; （b）在亲核催化剂存在下使游离的3'氨基与3'-保护的氨基二核苷酸-5'-亚磷酰胺二聚体接触以形成核苷间N 3'→P 5'亚磷酰胺连接; 和（c）氧化（例如硫化）连接。 通过本发明方法制备的组合物可以包括减少量的一种或多种（N-x）寡核苷酸产物。 还提供了包含本发明的寡核苷酸组合物的药物组合物。

    SPLICE-REGION ANTISENSE COMPOSITION AND METHOD
    102.
    发明申请
    SPLICE-REGION ANTISENSE COMPOSITION AND METHOD 有权
    区域抗体组合物和方法

    公开(公告)号：US20150232839A1

    公开(公告)日：2015-08-20

    申请号：US14535098

    申请日：2014-11-06

    申请人： Sarepta Therapeutics, Inc.

    发明人： Patrick L. Iversen ,  Robert Hudziak

    IPC分类号： C12N15/113

    CPC分类号： C12N15/113 ,  A61K38/00 ,  C07F9/65583 ,  C12N15/1132 ,  C12N15/1135 ,  C12N15/1136 ,  C12N15/1138 ,  C12N2310/11 ,  C12N2310/314 ,  C12N2310/3145 ,  C12N2310/3233 ,  C12N2320/33

    摘要： Antisense compositions targeted against an mRNA sequence coding for a selected protein, at a region having its 5′ end from 1 to about 25 base pairs downstream of a normal splice acceptor junction in the preprocessed mRNA, are disclosed. The antisense compound is RNase-inactive, and is preferably a phosphorodiamidate-linked morpholino oligonucleotide. Such targeting is effective to inhibit natural mRNA splice processing, produce splice variant mRNAs, and inhibit normal expression of the protein.

    摘要翻译： 公开了针对编码所选蛋白质的mRNA序列的反义组合物，其在其预处理的mRNA中正常剪接受体下游的1至约25个碱基对的其5'端的区域。 反义化合物是RNase-非活性的，优选为与二亚甲基二酰胺连接的吗啉代寡核苷酸。 这种靶向对于抑制天然的mRNA剪接加工，产生剪接变体mRNAs和抑制蛋白质的正常表达是有效的。

    ANTISENSE COMPOSITION AND METHOD FOR TREATING MUSCLE ATROPHY
    103.
    发明申请
    ANTISENSE COMPOSITION AND METHOD FOR TREATING MUSCLE ATROPHY 审中-公开
    用于治疗肌肉痉挛症的抗体组合物和方法

    公开(公告)号：US20150119316A1

    公开(公告)日：2015-04-30

    申请号：US14323349

    申请日：2014-07-03

    申请人： Sarepta Therapeutics, Inc.

    发明人： Patrick L. Iversen ,  Dwight D. Weller ,  Alan P. Timmins

    IPC分类号： C12N15/113 ,  C12Q1/68 ,  C07K7/08

    CPC分类号： C12N15/1136 ,  A61K31/675 ,  A61K47/645 ,  C07H21/00 ,  C07K7/08 ,  C12N2310/11 ,  C12N2310/31 ,  C12N2310/3145 ,  C12N2310/3233 ,  C12N2310/3513 ,  C12N2320/30 ,  C12Q1/6876 ,  C12Q2600/158 ,  Y10T436/143333

    摘要： A method and compound for treating skeletal muscle mass deficiency in a human subject are disclosed. The composition is an oligomer of morpholino subunits and phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ exocyclic carbon of an adjacent subunit, contains between 10-40 nucleotide bases, has a base sequence effective to hybridize to an expression-sensitive region of processed or preprocessed human myostatin RNA transcript, identified, in its processed form, by SEQ ID NO:6, and is capable of uptake by target muscle cells in the subject. In practicing the method, the compound is administered in an amount and at a dosage schedule to produce an overall reduction in the level of serum myostatin measured in the patient, and preferably to bring the myostatin level within the a range determined for normal, healthy individuals.

    摘要翻译： 公开了一种用于治疗人类受试者骨骼肌质量不足的方法和化合物。 该组合物是吗啉代亚基的低聚物和将一个亚基的吗啉代氮连接到相邻亚单位的5'环外碳的含磷亚基间键，含有10-40个核苷酸碱基之间，具有有效地与表达杂交的碱基序列 经处理或预处理的人肌生成抑制素RNA转录物的敏感区域，以其加工形式由SEQ ID NO：6鉴定，并且能够被摄体中的靶肌细胞摄取。 在实施该方法中，化合物以量和剂量方案施用以产生在患者体内测量的血清肌生成抑制素水平的总体降低，优选使肌生成抑制素水平在正常健康个体确定的范围内 。

    OLIGONUCLEOTIDE ANALOG AND METHOD FOR TREATING FLAVIVIRUS INFECTIONS
    105.
    发明申请
    OLIGONUCLEOTIDE ANALOG AND METHOD FOR TREATING FLAVIVIRUS INFECTIONS 有权
    寡核苷酸类似物和治疗感染病毒的方法

    公开(公告)号：US20150038462A1

    公开(公告)日：2015-02-05

    申请号：US14103603

    申请日：2013-12-11

    申请人： Sarepta Therapeutics, Inc.

    发明人： Patrick L. Iversen ,  David A. Stein

    IPC分类号： C12N15/113

    CPC分类号： C12N15/1131 ,  C12N2310/11 ,  C12N2310/314 ,  C12N2310/3145 ,  C12N2310/3233

    摘要： A method of inhibiting replication of a flavivirus in animal cells, and an oligonucleotide compound for use in the method are disclosed. The oligonucleotide analog (i) has a nuclease-resistant backbone, (ii) is capable of uptake by the cells, (iii) contains between 8-40 nucleotide bases, and (iv) has a sequence of at least 8 bases complementary to a region of the virus' positive strand RNA genome that includes at least a portion of SEQ ID NOS:1-4. Exposure of cells infected with a flavivirus to the analog is effective to form within the cells, a heteroduplex structure composed of the virus ssRNA and the oligonucleotide, characterized by a Tm of dissociation of at least 45° C., and having disrupted base pairing between the virus's 5′ and 3′ cyclization sequences.

    摘要翻译： 公开了抑制黄病毒在动物细胞中的复制的方法和用于该方法的寡核苷酸化合物。 寡核苷酸类似物（i）具有核酸酶抗性主链，（ii）能够被细胞吸收，（iii）含有8-40个核苷酸碱基，和（iv）具有至少8个碱基互补的序列 包含SEQ ID NO：1-4的至少一部分的病毒“正链RNA”基因组的区域。 用黄病毒感染的细胞暴露于类似物是有效的在细胞内形成，由病毒ssRNA和寡核苷酸组成的异源双链结构，其特征在于解离的Tm至少为45℃，并且具有中间的碱基配对 病毒的5'和3'环化序列。

    Peptide conjugated, inosine-substituted antisense oligomer compound and method
    107.
    发明授权
    Peptide conjugated, inosine-substituted antisense oligomer compound and method 有权
    肽缀合的，肌苷取代的反义寡聚体化合物和方法

    公开(公告)号：US08877725B2

    公开(公告)日：2014-11-04

    申请号：US13243341

    申请日：2011-09-23

    申请人： Patrick L. Iversen ,  Dwight D. Weller ,  Jed N. Hassinger

    发明人： Patrick L. Iversen ,  Dwight D. Weller ,  Jed N. Hassinger

    IPC分类号： C12N15/113 ,  C12N15/11 ,  A61K48/00

    CPC分类号： C12N15/113 ,  A61K48/0008 ,  C12N15/111 ,  C12N15/1135 ,  C12N2310/11 ,  C12N2310/3145 ,  C12N2310/3233 ,  C12N2310/331 ,  C12N2310/3513 ,  C12N2320/32

    摘要： A therapeutic oligomer-peptide conjugate, and methods of using the conjugate are disclosed. The conjugate includes (a) a substantially uncharged oligonucleotide analog compound having a base sequence that includes a string of bases that are complementary to four or more contiguous cytosine bases in a target nucleic acid region to which the compound is intended to bind, and (b) conjugated to the compound, an arginine-rich peptide effective to enhance the uptake of the compound into target cells. The string of bases in the compound includes at least one inosine base positioned in the string so as to limit the number of contiguous guanine bases in said string to three or fewer. The conjugate has greater cellular uptake than the compound alone, by virtue of the arginine-rich peptide, and substantially greater antisense activity greater activity than the conjugate in the absence of inosine-for guanine substitutions.

    摘要翻译： 公开了治疗性低聚物 - 肽缀合物和使用该缀合物的方法。 缀合物包括（a）具有碱基序列的基本上不带电的寡核苷酸类似物化合物，其碱基序列包括与化合物所要结合的靶核酸区域中的四个或更多个连续胞嘧啶碱基互补的碱基序列，和（b ），富含精氨酸的肽有效地增强化合物进入靶细胞的摄取。 所述化合物中的碱基串包括位于所述串中的至少一个肌苷碱基，以将所述串中的连续鸟嘌呤碱基的数量限制为三个或更少。 通过富含精氨酸的肽，缀合物比单独的化合物具有更大的细胞摄取，并且在不存在肌苷 - 用于鸟嘌呤取代的情况下，具有比缀合物更大的反义活性。

    SPLICE-REGION ANTISENSE COMPOSITION AND METHOD
    108.
    发明申请
    SPLICE-REGION ANTISENSE COMPOSITION AND METHOD 有权
    区域抗体组合物和方法

    公开(公告)号：US20140045916A1

    公开(公告)日：2014-02-13

    申请号：US13859518

    申请日：2013-04-09

    申请人： Sarepta Therapeutics, Inc.

    发明人： Patrick L. Iversen ,  Robert Hudziak

    IPC分类号： C12N15/113

    CPC分类号： C12N15/113 ,  A61K38/00 ,  C07F9/65583 ,  C12N15/1132 ,  C12N15/1135 ,  C12N15/1136 ,  C12N15/1138 ,  C12N2310/11 ,  C12N2310/314 ,  C12N2310/3145 ,  C12N2310/3233 ,  C12N2320/33

    摘要： Antisense compositions targeted against an mRNA sequence coding for a selected protein, at a region having its 5′ end from 1 to about 25 base pairs downstream of a normal splice acceptor junction in the preprocessed mRNA, are disclosed. The antisense compound is RNase-inactive, and is preferably a phosphorodiamidate-linked morpholino oligonucleotide. Such targeting is effective to inhibit natural mRNA splice processing, produce splice variant mRNAs, and inhibit normal expression of the protein.

    摘要翻译： 公开了针对编码所选蛋白质的mRNA序列的反义组合物，其在其预处理的mRNA中正常剪接受体下游的1至约25个碱基对的其5'端的区域。 反义化合物是RNase-非活性的，优选为与二亚甲基二酰胺连接的吗啉代寡核苷酸。 这种靶向对于抑制天然的mRNA剪接加工，产生剪接变体mRNAs和抑制蛋白质的正常表达是有效的。