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1. 发明申请

WO1995027480A1 HEME-BEARING MICROPARTICLES FOR TARGETED DELIVERY OF DRUGS 审中-公开
标题翻译：用于药物递送的HEME-BEARING MICROPARTICLES
公开(公告)号：WO1995027480A1
公开(公告)日：1995-10-19
申请号：PCT/US1995004315
申请日：1995-04-12
申请人： INNOVIR LABORATORIES, INC.
发明人： INNOVIR LABORATORIES, INC. , TAKLE, Garry, B. , GEORGE, Shaji, T.
IPC分类号： A61K09/16
CPC分类号： A61K9/1271 , A61K9/167 , A61K47/546 , A61K47/6911
摘要： Methods and compositions are described for the directed delivery of ribozymes or other compounds to specific cells which express the heme receptor on their surface using heme-bearing microparticles. Such microparticles are useful in the directed delivery and accumulation of drugs designed to treat hepatic diseases such as viral hepatitis or hepatoma.
摘要翻译：描述了用于将核酶或其他化合物定向递送到使用含血红素微粒在其表面上表达血红素受体的特定细胞的方法和组合物。这样的微粒可用于设计用于治疗肝病例如病毒性肝炎或肝癌的药物的定向递送和积累。

2. 发明申请

WO1997033622A2 DELIVERY OF NUCLEIC ACIDS BY PORPHYRINS 审中-公开
标题翻译：通过PORPHYRINS交付核酸
公开(公告)号：WO1997033622A2
公开(公告)日：1997-09-18
申请号：PCT/US1997004000
申请日：1997-03-14
申请人： INNOVIR LABORATORIES, INC. , TAKLE, Garry, B. , GEORGE, Shaji, T.
发明人： INNOVIR LABORATORIES, INC.
IPC分类号： A61K47/48
CPC分类号： A61K47/546
摘要： Efficient methods and compositions are provided for the targeted delivery of effective concentrations of compounds, including nucleic acid molecules and oligonucleotides such as EGSs, ribozymes and antisense, proteins, peptides, carbohydrate, and synthetic organic and inorganic molecules, or combinations thereof, to cells, especially hepatocytes. In the preferred embodiment, the compound is a negatively charged oligonucleotide which binds in a stoichiometric ratio to a water soluble, positively charged macrocycle such as a porphyrin, which targets and protects the oligonucleotide. The porphyrin protects the compound to be delivered and delivers the compound preferentially to certain cells and tissue types. In another embodiment, the porphyrin has anti-human hepatitis virus activity, when administered alone, which is significantly enhanced when in combination with an antiviral compound, especially an oligonucleotide.
摘要翻译：提供了有效的方法和组合物，用于靶向递送有效浓度的化合物，包括核酸分子和寡核苷酸，例如EGS，核酶和反义，蛋白质，肽，碳水化合物和合成的有机和无机分子或其组合，特别是肝细胞。在优选的实施方案中，化合物是以化学计量比与以水溶性，带正电荷的大环如卟啉结合的带负电荷的寡核苷酸，靶向并保护寡核苷酸。卟啉保护待递送的化合物，并将化合物优先递送至某些细胞和组织类型。在另一个实施方案中，当单独施用时，卟啉具有抗人肝炎病毒活性，当与抗病毒化合物，特别是寡核苷酸组合时，其显着增强。

3. 发明申请

WO1991004324A1 RIBOZYME COMPOSITIONS AND METHODS FOR USE 审中-公开
标题翻译： RIBOZYME组合物和使用方法
公开(公告)号：WO1991004324A1
公开(公告)日：1991-04-04
申请号：PCT/US1990005437
申请日：1990-09-25
申请人： INNOVIR LABORATORIES, INC.
发明人： INNOVIR LABORATORIES, INC. , ROBERTSON, Hugh, D. , GOLDBERG, Allan, R.
IPC分类号： C12N09/22
CPC分类号： C12N15/1132 , A61K38/00 , C07K14/005 , C07K2319/00 , C12N2310/111 , C12N2310/123 , C12N2740/16022 , C12N2760/10122
摘要： Ribozymes, sequences cleaving RNA, derived from sequences present in the hepatitis delta virus, have been engineered for greater specificity without increasing size. The specific ribozyme sequences are useful as reagents for cleaving RNA for experimental studies as well as antiviral therapies. Examples demonstrating the targeting of these sequences against HIV and Crohn's disease are described in detail. The sequences are also useful as diagnostics for the detection of hepatitis delta virus in tissue and fluid samples, as in blood banking, as well as in isolation and characterization of new viroids having ribozyme activity, using an RNA specific hybridization method. Based on analysis of the two domain structure of the hepatitis delta virus, it is possible to construct a vector for expression of non-hepatitis delta virus proteins in mammalian cells.

4. 发明申请

WO1996021731A2 STABILIZED EXTERNAL GUIDE SEQUENCES 审中-公开
标题翻译：稳定的外部指南序列
公开(公告)号：WO1996021731A2
公开(公告)日：1996-07-18
申请号：PCT/US1996000513
申请日：1996-01-16
申请人： INNOVIR LABORATORIES, INC. , GEORGE, Shaji, T. , MA, Michael , WERNER, Martina , PACE, Umberto , GOLDBERG, Allan, R.
发明人： INNOVIR LABORATORIES, INC.
IPC分类号： C12N15/11
CPC分类号： C12N15/113 , A61K38/00 , C12N15/1131 , C12N2310/111 , C12N2310/126 , C12N2310/315 , C12N2310/317 , C12N2310/321 , C12N2310/3535 , C12N2799/028 , C12N2310/3521
摘要： Modified external guide sequence (EGS) molecules that mediate cleavage of specific target RNAs have been constructed. The modified molecules are external guide sequence molecules for RNAse P which are designed to specifically bind to and promote RNAse P-mediated cleavage of target RNA molecules and to have enhanced nuclease resistance. Specific regions are modified to achieve enhanced stability while maintaining RNAse P activity. Modified external guide sequence molecules suitable for use in the treatment of hepatitis B viral infections have been constructed.
摘要翻译：已经构建了介导特异性靶RNA切割的修饰的外部引导序列（EGS）分子。修饰的分子是RNAse P的外部引导序列分子，其被设计为特异性结合并促进RNA酶P介导的靶RNA分子的切割并具有增强的核酸酶抗性。修改特定区域以实现增强的稳定性，同时保持RNAse P活性。已经构建了适用于治疗乙型肝炎病毒感染的改良外引导序列分子。

5. 发明申请

WO1996018733A3 RIBOZYME-MEDIATED INACTIVATION OF LEUKEMIA-ASSOCIATED RNA 审中-公开
公开(公告)号：WO1996018733A3
公开(公告)日：1996-06-20
申请号：PCT/US1995016451
申请日：1995-12-14
申请人： INNOVIR LABORATORIES, INC.
发明人： INNOVIR LABORATORIES, INC. , PACE, Umberto , GEORGE, Shaji, T. , GOLDBERG, Allan, R.
IPC分类号： C12N15/52

6. 发明申请

WO1994013833A1 RIBOZYME AMPLIFIED DIAGNOSTICS 审中-公开
标题翻译： RIBOZYME放大诊断
公开(公告)号：WO1994013833A1
公开(公告)日：1994-06-23
申请号：PCT/US1993011775
申请日：1993-12-03
申请人： INNOVIR LABORATORIES, INC.
发明人： INNOVIR LABORATORIES, INC. , SHIH, Andy , BOCKMAN, Jeffrey, M. , GEORGE, Shaji, T.
IPC分类号： C12Q01/68
CPC分类号： C12N15/113 , C12N2310/121 , C12N2310/3517 , C12Q1/6823 , C12Q2521/337
摘要： A system is described for the use of a ribozyme as a diagnostic tool for detecting the presence of a nucleic acid, protein, or other molecule, in which the formation of an active ribozyme and cleavage of an assayable marker is dependent on the presence or absence of the specific target molecule. The essential component is a ribozyme specifically but reversibly binding a selected target in combination with a labelled co-target, preferably immobilized on a support structure. When both the target and co-target are bound, the ribozyme cleaves the label from the co-target, which is then quantifiable. Since the ribozyme is reversibly bound by target and co-target, it can reassociate with additional co-target, cleaving more label, thereby amplifying the reaction signal. In one embodiment, the target is a nucleic acid hybridizing to complementary sequences that form part of the ribozyme; in a second embodiment, the target is a protein or other macromolecule which is bound by interactions with a portion of the ribozyme molecule. In another embodiment, a thermostable ribozyme is used, so that improperly bound ribozyme is destabilized and inactive at elevated temperatures. A method for isolating regulatable ribozymes is also disclosed. The regulatable ribozymes are useful in the method for detecting the presence of a specific macromolecule, or can be used in in vitro or in vivo methods for inactivation or activation of the cleavage of target RNA molecules.
摘要翻译：描述了使用核酶作为检测核酸，蛋白质或其他分子的存在的诊断工具的系统，其中活性核酶的形成和可测定标记物的切割取决于存在或不存在的特异性靶分子。基本组分是特异性的核酶，可逆地结合选定的靶标与标记的共靶标，优选固定在载体结构上。当目标靶标和共靶点都被结合时，核酶将共同靶标的标记物切割，然后可以对其进行定量。由于核酶可被靶和共靶标可逆地结合，因此可以与另外的共靶标重新结合，切割更多的标记物，从而扩增反应信号。在一个实施方案中，靶是与形成核酶的一部分的互补序列杂交的核酸; 在第二个实施方案中，靶是通过与一部分核酶分子相互作用而结合的蛋白质或其它大分子。在另一个实施方案中，使用热稳定性核酶，因此不正确结合的核酶在升高的温度下不稳定和无活性。还公开了一种用于分离可调节的核酶的方法。可调节的核酶可用于检测特异性大分子的存在的方法，或可用于体外或体内用于灭活或活化靶RNA分子切割的方法。

7. 发明申请

WO1998006440A2 PHENOTYPIC CONVERSION OF CELLS MEDIATED BY EXTERNAL GUIDE SEQUENCES 审中-公开
标题翻译：由外部指南序列介导的细胞的PHENOTYPIC转换
公开(公告)号：WO1998006440A2
公开(公告)日：1998-02-19
申请号：PCT/US1997014457
申请日：1997-08-15
申请人： INNOVIR LABORATORIES, INC.
发明人： INNOVIR LABORATORIES, INC. , TAKLE, Garry, B. , GOLDBERG, Allan, R. , GEORGE, Shaji, T.
IPC分类号： A61K47/48
CPC分类号： C12N15/1137 , A61K38/00 , C12N2310/111 , C12N2310/12 , C12N2310/126 , C12N2310/127 , Y02A50/481
摘要： Disclosed are a method and compositions for delivering nucleic acids to bacterial cells. The method does not require manipulation of the bacteria and is therefore particularly suited to delivery of nucleic acids to bacteria in natural environments, including inside animal bodies. The method generally involves conjugating the nucleic acid to be delivered with a cationic porphyrin and bringing the conjugate and the target bacterial cells into contact. Both the porphyrin and conjugated nucleic acid are taken up by the bacterial cells and the nucleic acid can then have a biological effect on the cells. Specifically disclosed is a method for converting drug-resistant bacterial cells to drug-sensitive cells by delivery of external guide sequences to the cells which then promote cleavage of RNA molecules involved in conferring the drug-resistant phenotype on the cells. The drug-resistant phenotype of the cells is thus converted to a drug-sensitive phenotype. The drug-sensitive cells are then susceptible to drug therapy. Also disclosed is a method and compositions for killing eukaryotic pathogens or converting drug-resistant eukaryotic cells to drug-sensitive cells. The method involves the delivery of external guide sequences, ribozymes, or vectors encoding external guide sequences or ribozymes, to eukaryotic cells. Preferred target eukaryotic cells for the disclosed method include algae, protozoa, fungi, slime mold, and cells of helminths.
摘要翻译：公开了将核酸递送至细菌细胞的方法和组合物。该方法不需要操纵细菌，因此特别适用于在自然环境（包括动物体内）向细菌递送核酸。该方法通常涉及将待递送的核酸与阳离子卟啉共轭并使缀合物和靶细菌细胞接触。卟啉和缀合的核酸都被细菌细胞吸收，核酸可以对细胞具有生物学作用。具体公开的是通过向细胞递送外部引导序列将耐药细菌细胞转化为药物敏感细胞的方法，其然后促进涉及赋予细胞耐药表型的RNA分子的切割。因此，细胞的抗药性表型被转化为药物敏感表型。药物敏感细胞对药物治疗敏感。还公开了用于杀死真核病原体或将药物抗性真核细胞转化为药物敏感细胞的方法和组合物。该方法涉及将外部引导序列，核酶或编码外部引导序列或核酶的载体递送至真核细胞。用于所公开方法的优选的靶真核细胞包括藻类，原生动物，真菌，粘液霉菌和蠕虫细胞。

8. 发明申请

WO1997033991A1 SHORT EXTERNAL GUIDE SEQUENCES 审中-公开
标题翻译：简短的外部指南序列
公开(公告)号：WO1997033991A1
公开(公告)日：1997-09-18
申请号：PCT/US1997003847
申请日：1997-03-14
申请人： INNOVIR LABORATORIES, INC. , WERNER, Martina , MA, Michael , GEORGE, Shaji, T.
发明人： INNOVIR LABORATORIES, INC.
IPC分类号： C12N15/11
CPC分类号： C12N15/113 , A61K38/00 , C12N2310/111 , C12N2310/126 , C12N2310/3125 , C12N2310/315 , C12N2310/316 , C12N2310/321 , C12N2310/322 , C12N2310/3527 , C12N2310/3521 , C12N2310/3523
摘要： External guide sequence (EGS) molecules for eukaryotic RNAse P are engineered to target efficient and specific cleavage of target RNA. Engineered RNA molecules are designed and synthesized which contain specific nucleotide sequences which enable an external guide sequence for RNAse P to preferentially bind to and promote RNAse P-mediated cleavage of target RNA molecules. Short External Guide Sequence (SEGS) molecules have been constructed that, when hybridized to a target molecule, provide a minimal structure recognized as a substrate by RNAse P. The SEGS/target structure is comprised of structures similar to the A stem and the T stem of a tRNA, the natural substrate of RNAse P. The SEGS makes up only half of these stem structures. The other half of the stem structures is provided by the target molecule. By allowing the target molecule to form more of the RNAse P substrate structure, the disclosed SEGS molecules can be significantly smaller than previous EGS molecules. This makes SEGS molecules especially useful as therapeutic agents since they are easier to manufacture and administer in quantity.
摘要翻译：用于真核RNA酶P的外部引导序列（EGS）分子被设计成靶向靶RNA的有效和特异性切割。设计和合成工程化RNA分子，其包含特异性核苷酸序列，其使RNAse P的外部引导序列优先结合并促进RNA酶P介导的靶RNA分子的切割。已经构建了短的外导向序列（SEGS）分子，当与靶分子杂交时，通过RNA酶P提供被认为是底物的最小结构.SEG /目标结构由类似于A茎和T茎的结构组成的tRNA是RNA酶P的天然底物.SEG仅占这些茎结构的一半。茎结构的另一半由靶分子提供。通过使靶分子形成更多的RNA酶P底物结构，所公开的SEGS分子可以显着小于先前的EGS分子。这使得SEGS分子特别用作治疗剂，因为它们更容易制造和施用量。

9. 发明申请

WO1994013791A1 REGULATABLE NUCLEIC ACID THERAPEUTIC AND METHODS OF USE THEREOF 审中-公开
标题翻译：可调节的核酸治疗方法及其使用方法
公开(公告)号：WO1994013791A1
公开(公告)日：1994-06-23
申请号：PCT/US1993011783
申请日：1993-12-03
申请人： INNOVIR LABORATORIES, INC.
发明人： INNOVIR LABORATORIES, INC. , GEORGE, Shaji, T. , SHIH, Andy , BOCKMAN, Jeffrey, M.
IPC分类号： C12N09/10
CPC分类号： C12N15/113 , A61K38/00 , C07K14/005 , C07K2319/00 , C12N2310/121 , C12N2730/10122
摘要： Construction of a regulatable ribozyme is described in which a ribozyme sequence is linked to a ligand-binding sequence, placing the activity of the ribozyme under the control of that ligand and requiring the presence of the ligand for activation or inactivation. RNA molecules are constructed in which one portion is capable of binding a ligand and the other portion is a ribozyme. After the selection of molecules which bind the ligand, a second selection process occurs in which the ligand-binding molecules are assayed for their catalytic function in the presence and absence of the ligand or "co-drug." In this manner regulatable ribozymes are selected for use in cleaving a target RNA in the presence of a ligand, or in cleaving a target RNA in the absence of a ligand. Thismethod and regulatable ribozymes are useful in cleaving a target RNA molecule in a controlled fashion. It is particularly useful when the target RNA molecule is present in a cell where it is not desirable to kill the host cell by complete inactivation of these RNA molecules.
摘要翻译：描述了可调节核酶的构建，其中核酶序列与配体结合序列连接，将核酶的活性置于该配体的控制下，并且需要存在配体用于活化或失活。构建RNA分子，其中一部分能够结合配体，另一部分是核酶。在选择结合配体的分子之后，进行第二选择过程，其中配体结合分子在存在和不存在配体或“共同药物”的情况下测定其催化功能。以这种方式，选择可配位的核酶在配体存在下切割靶RNA，或在不存在配体的情况下切割靶RNA。该方法和可调节的核酶可用于以受控的方式切割靶RNA分子。当靶RNA分子存在于通过完全灭活这些RNA分子不希望杀死宿主细胞的细胞中时，这是特别有用的。

10. 发明申请

WO1991004319A1 THERAPEUTIC RIBOZYME COMPOSITIONS AND EXPRESSION VECTORS 审中-公开
标题翻译：治疗RIBOZYME组合物和表达载体
公开(公告)号：WO1991004319A1
公开(公告)日：1991-04-04
申请号：PCT/US1990005450
申请日：1990-09-25
申请人： INNOVIR LABORATORIES, INC.
发明人： INNOVIR LABORATORIES, INC. , GOLDBERG, Allan, R. , GEORGE, Shaji, T. , ROBERTSON, Hugh, D.
IPC分类号： C12N07/01
CPC分类号： C12N15/1132 , A61K38/00 , A61K47/6901 , A61K48/00 , C07K14/005 , C07K2319/00 , C12N15/1131 , C12N15/86 , C12N2310/111 , C12N2310/123 , C12N2730/10122 , C12N2730/10134 , C12N2740/16043 , C12N2740/16122 , C12N2740/16222 , C12N2760/10122 , C12N2760/10134
摘要： Hepatitis delta is used as a vector for inhibition of viral infection and to express proteins in vivo in a cell-specific manner. The scope of delta's use as a vector is broadened in the present invention in several important ways. For example, a delta RNA genome capable of self-replication is enlarged to carry additional information, either coding for messenger RNA for a protein, or for a targeted ribozyme, which can be delivered to liver cells using delta's normally infectious properties, or to other cell types using chimeric delta viral agents carrying altered surface proteins. In another embodiment, the delta vector is made self-limiting, so that its role in delivering targeted information is separated from its viral property of unlimited infectious replication. Targeting is achieved through the use of sequences flanking the delta sequences that have affinity for sites on RNA to be cleaved.

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