公开(公告)号：US06686338B1

公开(公告)日：2004-02-03

申请号：US09574570

申请日：2000-05-17

申请人： Patrick L. Iversen

发明人： Patrick L. Iversen

IPC分类号： A61K3170

CPC分类号： C12N15/1137 ,  A61K31/337 ,  A61K38/00 ,  C12N2310/314 ,  C12N2310/3233 ,  A61K2300/00

摘要： A method is described for improving the pharmacokinetics of a drug in a subject, by co-administering oligomers, preferably PMO's (phosphorodiamidate morpholino oligonucleotides), antisense to RNAs encoding drug-metabolizing enzymes, particularly p450 enzymes. The oligomers reduce production of the drug-metabolizing enzymes, which extends drug half-life and effectiveness and/or decreases drug toxicity.

摘要翻译： 描述了通过共同施用寡核苷酸（优选PMO（磷酸二甲酯吗啉代寡核苷酸））来改善受试者中药物的药代动力学的方法，其与编码药物代谢酶，特别是p450酶的RNA反义。 寡聚物减少药物代谢酶的产生，其延长了药物的半衰期和有效性和/或降低了药物毒性。

公开(公告)号：US06365351B1

公开(公告)日：2002-04-02

申请号：US09493494

申请日：2000-01-28

申请人： Patrick L. Iversen

发明人： Patrick L. Iversen

IPC分类号： C12Q168

CPC分类号： C12N15/113 ,  A61K38/00 ,  C12N15/1135 ,  C12N2310/314 ,  C12N2310/3233 ,  C12N2310/3517 ,  C12Q1/6883 ,  C12Q2600/158

摘要： The present invention provides a method for targeting a particular mRNA sequence in vivo by oral administration of a morpholino antisense compound having uncharged phosphorus-containing backbone linkages. Also disclosed is a non-invasive method of detecting and quantitating the in vivo presence of RNA containing one or more selected target sequences. The method includes administering to a subject a nuclease-resistant antisense oligomer which hybridizes by Watson-Crick base pairing to a region of the target RNA with a Tm substantially greater than 37° C. The oligomer is able to complex intracellularly with target RNA, and is released from intracellular sites as a nuclease-resistant heteroduplex, which can then be measured in a body fluid sample, e.g., urine.

摘要翻译： 本发明提供了通过口服施用具有不带电荷的含磷骨架键的吗啉代反义化合物来靶向体内特定mRNA序列的方法。 还公开了检测和定量含有一种或多种所选靶序列的RNA的体内存在的非侵入性方法。 该方法包括向受试者施用核酸酶抗性反义低聚体，其通过Watson-Crick碱基配对与目标RNA的区域以Tm基本上大于37℃杂交。寡聚体能够用靶RNA细胞内复合，并且 作为核酸酶抗性异源双链体从胞内位点释放，然后可以在体液样品（例如尿液）中测量。

公开(公告)号：US5849727A

公开(公告)日：1998-12-15

申请号：US670999

申请日：1996-06-28

申请人： Thomas R. Porter ,  Patrick L. Iversen

发明人： Thomas R. Porter ,  Patrick L. Iversen

IPC分类号： A61K47/42 ,  A61K9/48 ,  A61K38/00 ,  A61K41/00 ,  A61K47/48 ,  A61K48/00 ,  A61K49/22 ,  A01N51/00

CPC分类号： A61K41/0028 ,  A61K47/48869 ,  A61K49/223

摘要： This invention relates to a new and improved pharmaceutical composition and method for delivery of therapeutic or bioactive agents. The methods and composition of the invention can be used with several therapeutic or bioactive agents and can achieve site-specific delivery of a therapeutic or biologically-active substance. This can allow for lower doses and for improved efficacy with drugs, particularly agents such as oligonucleotides which are plagued with problems in achieving therapeutic levels at targeted sites.

摘要翻译： 本发明涉及用于递送治疗或生物活性剂的新的和改进的药物组合物和方法。 本发明的方法和组合物可以与几种治疗或生物活性剂一起使用，并且可以实现治疗或生物活性物质的位点特异性递送。 这可以允许较低的剂量和用于药物，特别是诸如寡核苷酸的药物的改善效果，这些药剂在靶点上达到治疗水平方面存在问题。

公开(公告)号：US09572899B2

公开(公告)日：2017-02-21

申请号：US12265499

申请日：2008-11-05

申请人： Patrick L. Iversen ,  Hong M. Moulton ,  Michelle H. Nelson ,  Andrew D. Kroeker ,  David A. Stein

发明人： Patrick L. Iversen ,  Hong M. Moulton ,  Michelle H. Nelson ,  Andrew D. Kroeker ,  David A. Stein

IPC分类号： A61K38/10 ,  C07K4/00 ,  A61K38/08 ,  C07H21/02 ,  A61K49/00 ,  A61K47/48 ,  C12N15/113 ,  C12N15/87

CPC分类号： A61K49/0056 ,  A61K47/64 ,  A61K49/0043 ,  A61K49/0054 ,  C12N15/113 ,  C12N15/87 ,  C12N2310/11 ,  C12N2310/314 ,  C12N2310/3233 ,  C12N2310/3513 ,  C12N2320/32

摘要： Compositions and methods for enhancing delivery of molecules, e.g. biological agents, into cells are described. The composition is a conjugate of the biological agent, preferably a nucleic acid analog having a substantially uncharged backbone, covalently linked to a peptide transporter moiety as described. Conjugation of the peptide transporter to a substantially uncharged nucleic acid analog, such as a morpholino oligomer, is also shown to enhance binding of the oligomer to its target sequence and enhance antisense activity.

摘要翻译： 用于增强分子递送的组合物和方法，例如 描述了生物制剂进入细胞。 组合物是生物制剂的缀合物，优选具有基本上不带电的主链的核酸类似物，其与所述的肽转运蛋白部分共价连接。 还显示肽转运蛋白与基本上不带电的核酸类似物如吗啉代低聚物的缀合增强寡聚物与其靶序列的结合并增强反义活性。

公开(公告)号：US09068185B2

公开(公告)日：2015-06-30

申请号：US13046356

申请日：2011-03-11

申请人： Patrick L. Iversen

发明人： Patrick L. Iversen

IPC分类号： C07H21/04 ,  C12N15/113

CPC分类号： C12N15/1138 ,  C12N2310/11 ,  C12N2310/314 ,  C12N2310/3233 ,  C12N2310/3513

摘要： Provided are antisense oligonucleotides and other agents that target and modulate nuclear hormone receptors (NHRs) such as the glucocorticoid receptor (GR), compositions that comprise the same, and methods of use thereof.

摘要翻译： 提供靶向和调节核激素受体（NHR）的反义寡核苷酸和其他试剂，例如糖皮质激素受体（GR），包含其的组合物及其使用方法。

公开(公告)号：US08618270B2

公开(公告)日：2013-12-31

申请号：US12848873

申请日：2010-08-02

申请人： Patrick L. Iversen ,  David A. Stein

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

IPC分类号： A61K31/70 ,  C07H21/04 ,  C12N5/00

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' 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'5'和3'环化序列。

公开(公告)号：US20130289091A1

公开(公告)日：2013-10-31

申请号：US13680790

申请日：2012-11-19

申请人： Bruce L. Geller ,  Jesse D. Deere ,  Patrick L. Iversen

发明人： Bruce L. Geller ,  Jesse D. Deere ,  Patrick L. Iversen

IPC分类号： C12N15/113

CPC分类号： C12N15/1137 ,  C07F9/65583 ,  C07F9/65613 ,  C12N15/113 ,  C12N2310/11 ,  C12N2310/3145 ,  C12N2310/3233

摘要： A method and antisense compound for inhibiting the growth of pathogenic bacterial cells are disclosed. The compound contains no more than 12 nucleotide bases and has a targeting nucleic acid sequence of no fewer than 10 bases in length that is complementary to a target sequence containing or within 10 bases, in a downstream direction, of the translational start codon of a bacterial mRNA that encodes a bacterial protein essential for bacterial replication. The compound binds to a target mRNA with a Tm of between 50° to 60° C. The relatively short antisense compounds are substantially more active than conventional antisense compounds having a targeting base sequence of 15 or more bases.

摘要翻译： 公开了一种用于抑制病原菌细胞生长的方法和反义化合物。 该化合物含有不超过12个核苷酸碱基，并且具有长度不小于10个碱基的靶向核酸序列，该靶向核酸序列与在细菌的翻译起始密码子的下游方向上含有或在10个碱基内的靶序列互补 编码细菌复制必需的细菌蛋白质的mRNA。 该化合物以Tm在50℃至60℃之间的靶mRNA结合。相对较短的反义化合物比具有15个或更多碱基的靶向碱基序列的常规反义化合物显着更具活性。

公开(公告)号：US08524676B2

公开(公告)日：2013-09-03

申请号：US11517757

申请日：2006-09-08

申请人： David A. Stein ,  Richard K. Bestwick ,  Patrick L. Iversen ,  Dwight D. Weller

发明人： David A. Stein ,  Richard K. Bestwick ,  Patrick L. Iversen ,  Dwight D. Weller

IPC分类号： C12N15/11 ,  A61K38/00 ,  C07H21/04

CPC分类号： A61K38/00 ,  C12N15/1131 ,  C12N2310/11 ,  C12N2310/314 ,  C12N2310/3233 ,  C12N2770/32311 ,  C12N2770/32711

摘要： The invention provides antisense antiviral compounds and methods of their use and production in inhibition of growth of viruses of the Picornaviridae family and in the treatment of a viral infection. The compounds are particularly useful in the treatment of Enterovirus and/or Rhinovirus infection in a mammal. The antisense antiviral compounds are substantially uncharged, morpholino oligonucleotides have a sequence of 12-40 subunits, including at least 12 subunits having a targeting sequence that is complementary to a region associated with viral RNA sequences within a 32 nucleotide region of the viral 5′ untranslated region identified by SEQ ID NO:7.

摘要翻译： 本发明提供反义抗病毒化合物及其在抑制小核糖核酸病毒科家族病毒生长和用于病毒感染治疗中的用途和生产方法。 所述化合物特别可用于治疗哺乳动物中的肠病毒和/或鼻病毒感染。 反义抗病毒化合物是基本上不带电的，吗啉代寡核苷酸具有12-40个亚基的序列，包括至少12个亚基，其具有与病毒5'非翻译的32个核苷酸区域内的病毒RNA序列相关的区域互补的靶向序列 由SEQ ID NO：7鉴定的区域。

公开(公告)号：US08357664B2

公开(公告)日：2013-01-22

申请号：US11259434

申请日：2005-10-25

申请人： David A. Stein ,  Qing Ge ,  Jianzhu Chen ,  Patrick L. Iversen ,  Hong M. Moulton

发明人： David A. Stein ,  Qing Ge ,  Jianzhu Chen ,  Patrick L. Iversen ,  Hong M. Moulton

IPC分类号： A61K48/00

CPC分类号： C12N15/1131 ,  C12N2310/3145 ,  C12N2310/3233 ,  C12N2310/3513

摘要： The invention provides antisense antiviral compounds and methods of their use and production in inhibition of growth of viruses of the Orthomyxoviridae family and in the treatment of a viral infection. The compounds are particularly useful in the treatment of influenza virus infection in a mammal. The antisense antiviral compounds are substantially uncharged morpholino oligonucleotides having 1) a nuclease resistant backbone, 2) 12-40 nucleotide bases, and 3) a targeting sequence of at least 12 bases in length that hybridizes to a target region selected from the following: a) the 5′ or 3′ terminal 25 bases of the negative sense viral RNA segment of Influenzavirus A, Influenzavirus B and Influenzavirus C; b) the terminal 25 bases of the 3′ terminus of the positive sense cRNA and; and c) the 50 bases surrounding the AUG start codon of an influenza viral mRNA.

摘要翻译： 本发明提供反义抗病毒化合物及其在抑制正粘病毒科的病毒生长和用于病毒感染治疗中的用途和生产方法。 该化合物特别可用于治疗哺乳动物的流感病毒感染。 反义抗病毒化合物是具有1）核酸酶抗性主链，2）12-40个核苷酸碱基的基本上不带电荷的吗啉代寡核苷酸，和3）长度为至少12个碱基的靶向序列与选自以下的靶区域杂交： ）流感病毒A，流感病毒B和流感病毒C的负义病毒RNA片段的5'或3'末端25个碱基; b）正义cRNA的3'末端的末端25个碱基; 和c）围绕流感病毒mRNA的AUG起始密码子的50个碱基。

公开(公告)号：US20130011420A1

公开(公告)日：2013-01-10

申请号：US13469892

申请日：2012-05-11

申请人： Patrick L. Iversen ,  Dwight D. Weller

发明人： Patrick L. Iversen ,  Dwight D. Weller

IPC分类号： C07H21/00 ,  A61K39/00 ,  A61P31/12 ,  A61K48/00

CPC分类号： C12N15/113 ,  A61K31/675 ,  A61K31/713 ,  C12N15/1131 ,  C12N2310/11 ,  C12N2310/3233

摘要： The present invention provides antisense antiviral compounds, compositions, and methods of their use and production, mainly for inhibiting the replication of viruses of the Filoviridae family, including Ebola and Marburg viruses. The compounds, compositions, and methods also relate to the treatment of viral infections in mammals including primates by Ebola and Marburg viruses. The antisense antiviral compounds include phosphorodiamidate morpholino oligonucleotides (PMOplus) having a nuclease resistant backbone, about 15-40 nucleotide bases, at least two but typically no more than half piperazine-containing intersubunit linkages, and a targeting sequence that is targeted against the AUG start site region of Ebola virus VP35, Ebola virus VP24, Marburg virus VP24, or Marburg virus NP, including combinations and mixtures thereof

摘要翻译： 本发明提供反义抗病毒化合物，组合物及其使用和生产方法，主要用于抑制丝状病毒科病毒的复制，包括埃博拉病毒和马尔堡病毒。 化合物，组合物和方法还涉及治疗包括埃博拉和马尔堡病毒在内的哺乳动物中的病毒感染。 反义抗病毒化合物包括具有核酸酶抗性主链的磷酸二亚胺吗啉代寡核苷酸（PMOplus），约15-40个核苷酸碱基，至少两个但通常不超过一半的含哌嗪的亚单位间连接，以及针对AUG起始靶向序列 埃博拉病毒VP35的位点区域，埃博拉病毒VP24，马尔堡病毒VP24或马尔堡病毒NP，包括其组合和混合物