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    USE OF RNA TRANS-SPLICING FOR ANTIBODY GENE TRANSFER AND ANTIBODY POLYPEPTIDE PRODUCTION
    1.
    发明申请
    USE OF RNA TRANS-SPLICING FOR ANTIBODY GENE TRANSFER AND ANTIBODY POLYPEPTIDE PRODUCTION 审中-公开
    RNA转导分离用于抗体基因转移和抗体多肽生产的应用

    公开(公告)号：WO2006083331A2

    公开(公告)日：2006-08-10

    申请号：PCT/US2005036215

    申请日：2005-10-07

    Applicant: INTRONN INC ,  MCGARRITY GERARD J ,  PUTTARAJU MADAIAH ,  GARCIA-BLANCO MARIANO A

    Inventor： MCGARRITY GERARD J ,  PUTTARAJU MADAIAH ,  GARCIA-BLANCO MARIANO A

    CPC classification number: C07K16/084 ,  A61K48/00 ,  A61K2039/505 ,  C07K16/00 ,  C07K2317/622 ,  C12N15/1027

    Abstract: The present invention provides methods and compositions for generating novel nucleic acid molecules through RNA trans-splicing that target a highly expressed pre-mRNA and contain the coding sequence for antibody polypeptide(s). The compositions of the invention include pre-trans-splicing molecules (PTMs) designed to interact with the target precursor messenger RNA molecule (target pre-mRNA) that is abundantly expressed or tumor specific and mediate a trans-splicing reaction resulting in the generation of novel chimeric RNA molecule (chimeric RNA) capable of encoding an antibody polypeptide. The invention provides for the in vivo production of chimeric RNA molecules that encode and result in the production of an antibody polypeptide that is therapeutically effective against, for example, infectious agents, cancer cells, transplantation antigens, rheumatoid arthritis, etc.

    Abstract translation: 本发明提供了通过针对高度表达的前mRNA并含有抗体多肽的编码序列的RNA反式剪接产生新的核酸分子的方法和组合物。 本发明的组合物包括设计成与大量表达或肿瘤特异性的靶前体信使RNA分子（靶前体mRNA）相互作用的转录前分子（PTM），并介导转拼反应，导致产生 能够编码抗体多肽的新型嵌合RNA分子（嵌合RNA）。 本发明提供了嵌合RNA分子的体内产生，所述嵌合RNA分子编码并导致抗体多肽的产生，所述抗体多肽对于例如感染因子，癌细胞，移植抗原，类风湿性关节炎等具有治疗有效性。

    EXPRESSION OF APOA-1 AND VARIANTS THEREOF USING SPLICEOSOME MEDIATED RNA TRANS-SPLICING
    2.
    发明申请
    EXPRESSION OF APOA-1 AND VARIANTS THEREOF USING SPLICEOSOME MEDIATED RNA TRANS-SPLICING 审中-公开

    公开(公告)号：WO2005070023A3

    公开(公告)日：2005-08-04

    申请号：PCT/US2005/002392

    申请日：2005-01-21

    Applicant: INTRONN, INC. ,  PUTTARAJU, Madaiah ,  OTTO, Edward ,  GARCIA-BLANCO, Mariano, A. ,  MCGARRITY, Gerard, J. ,  TEMPLE, Gary, F. ,  MITCHELL, Lloyd, G.

    Inventor： PUTTARAJU, Madaiah ,  OTTO, Edward ,  GARCIA-BLANCO, Mariano, A. ,  MCGARRITY, Gerard, J. ,  TEMPLE, Gary, F. ,  MITCHELL, Lloyd, G.

    IPC: C07H21/02

    Abstract: The present invention provides methods and compositions for generating novel nucleic acid molecules through targeted spliceosome mediated RNA trans -splicing that result in expression of an apoA-1 variant, the preferred embodiment referred to herein as the apoA-1 Milano variant. The compositions of the invention include pre- trans -splicing molecules (PTMs) designed to interact with a target precursor messenger RNA molecule (target pre-mRNA) and mediate a trans­- splicing reaction resulting in the generation of a novel chimeric RNA molecule (chimeric RNA) capable of encoding the apoA-1 Milano variant. The expression of this variant protein results in protection against vascular disorders resulting from plaque build up, i.e., strokes and heart attacks. In particular, the PTMs of the presént invention include those genetically engineered to interact with the apoA-1 target pre­mRNA so as to result in expression of the apoA-1 Milano variant. In addition, the PTMs of the invention include those genetically engineered to interact with the apoB or albumin or other specific target pre-mRNAs so as to result in expression of an apoB/apoA-1 and/or alb/apoA-1 wild type or Milano fusion protein thereby reducing apoB expression and simultaneously produce ApoA-1 function.

    SPLICEOSOME MEDIATED RNA TRANS-SPLICING AND CORRECTION OF FACTOR VIII GENETIC DEFECTS
    5.
    发明申请
    SPLICEOSOME MEDIATED RNA TRANS-SPLICING AND CORRECTION OF FACTOR VIII GENETIC DEFECTS 审中-公开

    公开(公告)号：WO2003104412A3

    公开(公告)日：2003-12-18

    申请号：PCT/US2003/017913

    申请日：2003-06-05

    Applicant: INTRONN, INC. ,  MITCHELL, Lloyd, G. ,  MANSFIELD, S. Gary ,  PUTTARAJU, Madaiah ,  CLARK, Rebecca ,  GARCIA-BLANCO, Mariano, A.

    Inventor： MITCHELL, Lloyd, G. ,  MANSFIELD, S. Gary ,  PUTTARAJU, Madaiah ,  CLARK, Rebecca ,  GARCIA-BLANCO, Mariano, A.

    IPC: C07H21/02

    Abstract: The compositions of the invention include pre- trans -splicing molecules (PTMs) designed to interact with a target precursor messenger RNA molecule (target pre-mRNA) and mediate a trans -splicing reaction resulting in the generation of a novel chimeric RNA molecule (chimeric RNA). In particular, the PTMs of the present invention are genetically engineered to interact with factor VIII (FVIII) target pre-mRNA so as to result in correction of clotting FVIII genetic defects responsible for hemophilia A. The compositions of the invention further include recombinant vector systems capable of expressing the PTMs of the invention and cells expressing said PTMs. The methods of the invention encompass contacting the PTMs of the invention with a FVIII target pre-mRNA under conditions in which a portion of the PTM is trans -spliced to a portion of the target pre-mRNA to form a RNA molecule wherein the genetic defect in the FVIII gene has been corrected. The methods and compositions of the present invention can be used in gene therapy for correction of FVIII disorders such as hemophilia A.

    TRANSGENIC ANIMAL MODEL FOR SPLICEOSOME-MEDIATED RNA TRANS-SPLICING
    6.
    发明申请
    TRANSGENIC ANIMAL MODEL FOR SPLICEOSOME-MEDIATED RNA TRANS-SPLICING 审中-公开
    用于SPLICEOSOME介导RNA转移分离的转基因动物模型

    公开(公告)号：WO03093414A2

    公开(公告)日：2003-11-13

    申请号：PCT/US0313161

    申请日：2003-04-30

    Applicant: INTRONN INC ,  PUTTARAJU MADAIAH ,  MITCHEL LLOYD ,  ENGELHARDT JOHN F ,  BLANCO MARIANO GARCIA ,  LIU XIAOMING

    Inventor： PUTTARAJU MADAIAH ,  MITCHEL LLOYD ,  ENGELHARDT JOHN F ,  BLANCO MARIANO GARCIA ,  LIU XIAOMING

    IPC: A01K67/027 ,  C12N15/09 ,  C12N15/85 ,  C12Q1/68 ,  C12N

    CPC classification number: C12N15/8509 ,  A01K67/0275 ,  A01K2217/05 ,  A01K2227/105 ,  A01K2267/0393 ,  C12N2800/30

    Abstract: The present invention relates to development of an animal model system for in vivo testing of spliceosome-mediated RNA trans-splicing reactions. The present invention provides transgenic animals, and methods for generating such animals, that have been genetically engineered to expresses a target precursor messenger RNA molecule (target pre-mRNA) that serves as a substrate for a trans-splicing reaction. Specifically, the transgenic animals contain at least one transgene capable of expressing a target pre-mRNA molecule. The invention provides methods, based on utilization of the transgenic animals, for assessing the specificity and efficiency of a pre-trans-splicing molecule (PTM) designed to interact with a target pre-mRNA and mediate a trans-splicing reaction resulting in the generation of a novel chimeric RNA molecule. The present invention further relates to the transgenic expression of PTM molecules in animals to determine gene function, i.e, functional genetics. The present invention is based on the successful generation of a transgenic animal expressing a target pre-mRNA and, moreover, the use of that animal to detect accurate in vivo trans-splicing reactions in the presence of a PTM.

    Abstract translation: 本发明涉及用于体内测试剪接体介导的RNA反式剪接反应的动物模型系统的开发。 本发明提供了转基因动物，以及用于产生这样的动物的方法，其被遗传工程化以表达用作转拼反应的底物的靶前体信使RNA分子（靶前体mRNA）。 具体地，转基因动物含有能够表达靶mRNA前分子的至少一个转基因。 本发明提供了基于转基因动物利用的方法，用于评估设计成与靶前体mRNA相互作用的转录前分子（PTM）的特异性和效率，并介导导致产生转录的反式剪接反应 的新型嵌合RNA分子。 本发明还涉及PTM分子在动物中的转基因表达以确定基因功能，即功能遗传学。 本发明基于成功生成表达靶mRNA的转基因动物，此外，该技术在PTM存在下使用该动物检测精确的体内转拼反应。

    TRANS-SPLICING MEDIATED IMAGING OF GENE EXPRESSION
    7.
    发明申请
    TRANS-SPLICING MEDIATED IMAGING OF GENE EXPRESSION 审中-公开

    公开(公告)号：WO2003072739A3

    公开(公告)日：2003-09-04

    申请号：PCT/US2003/005615

    申请日：2003-02-25

    Applicant: INTRONN, INC. ,  MITCHELL, Lloyd, G. ,  PUTTARAJU, Madaiah ,  MANSFIELD, Gary, S.

    Inventor： MITCHELL, Lloyd, G. ,  PUTTARAJU, Madaiah ,  MANSFIELD, Gary, S.

    IPC: C07H21/02

    Abstract: The present invention provides methods and compositions for imaging of gene expression in cells. The compositions of the invention include pre-trans­splicing molecules (PTMs) designed to interact with a target precursor messenger RNA molecule (target pre-mRNA) expressed within a cell and mediate a trans­splicing reaction resulting in the generation of a novel chimeric RNA molecule (chimeric RNA) capable of encoding a reporter molecule. The PTMs of the invention are designed to interact with target pre-mRNAs thereby providing a method for detection of target pre-mRNA expression. The methods and compositions of the invention may be utilized to monitor the expression of specific genes within a cell. In instances where specific gene expression is associated with a disease, the present invention provides diagnostic methods and compositions. Such diseases include infectious diseases, proliferative disorders such as cancer, genetic, neurological and metabolic disorders, to name a few. Additionally, the present invention may be used in screening assays to identify compounds capable of modulating gene expression or in assays designed to identify protein/protein interactions. The invention is demonstrated by way of example in which papilloma virus gene expression within a cell was detected using a bioluminescence assay system.

    SCREENING METHODS FOR IDENTIFICATION OF EFFICIENT PRE-TRANS-SPLICING MOLECULES
    9.
    发明申请
    SCREENING METHODS FOR IDENTIFICATION OF EFFICIENT PRE-TRANS-SPLICING MOLECULES 审中-公开
    用于识别有效预分离分子的筛选方法

    公开(公告)号：WO2004038380A2

    公开(公告)日：2004-05-06

    申请号：PCT/US0334102

    申请日：2003-10-23

    Applicant: INTRONN INC ,  MITCHELL LLOYD G ,  PUTTARAJU MADAIAH ,  GARCIA-BLANCO MARIANO ,  OTTO EDWARD ,  YANG YANPING

    Inventor： MITCHELL LLOYD G ,  PUTTARAJU MADAIAH ,  GARCIA-BLANCO MARIANO ,  OTTO EDWARD ,  YANG YANPING

    IPC: C07H21/04 ,  C12Q1/68 ,  G01N20060101 ,  G01N33/50 ,  G01N33/53 ,  G01N

    CPC classification number: C12N15/1027 ,  C12N15/1086 ,  G01N33/5023

    Abstract: The present invention provides methods and compositions for rapid high capacity functional screening to identify optimal pre-trans-splicing molecules (PTMs). The compositions of the invention include PTM expression libraries capable of encoding candidate PTMs designed to interact with a target precursor messenger RNA molecule (target pre-mRNA) and mediate a trans-splicing reaction resulting in the generation of a novel chimeric RNA molecule (chimeric RNA). The candidate PTMs of the invention encode a portion of a first reporter molecule and may encode one or more other reporter molecules, which can be used to select for cells expressing optimal PTMs (efficient and specific). The compositions of the invention also include cells that express a target pre-mRNA encoding the remaining portion of the first reporter molecule. The screening methods of the invention encompass (i) contacting a PTM expression library with cells expressing a target pre-mRNA under conditions in which a trans-splicing reaction will occur in the presence of an optimal PTM (expressed by the library vector) resulting in the formation of a chimeric repaired RNA molecule capable of encoding at least one reporter molecule; (ii) selecting for cells expressing the repaired reporter molecule wherein expression of the reporter molecule indicates the presence of an optimal PTM in the selected cell; and (iii) identifying the optimal PTM expressed in the selected cell(s). The additional reporter molecule(s) can be used to assess both specific and non-specific trans-splicing, as well direct PTM expression.

    Abstract translation: 本发明提供用于快速高容量功能筛选以鉴定最佳预转录分子（PTM）的方法和组合物。 本发明的组合物包括能够编码设计成与靶前体信使RNA分子（靶前体mRNA）相互作用的候选PTM的PTM表达文库，并介导产生新型嵌合RNA分子的转拼反应（嵌合RNA ）。 本发明的候选PTM编码第一报告分子的一部分并且可以编码一个或多个其它报告分子，其可用于选择表达最佳PTM（有效和特异性）的细胞。 本发明的组合物还包括表达编码第一报告分子的剩余部分的靶mRNA的细胞。 本发明的筛选方法包括（i）在最优PTM（由文库载体表达）存在下在其中将发生转拼反应的条件下使PTM表达文库与表达靶mRNA的细胞接触，导致 形成能够编码至少一个报告分子的嵌合修复的RNA分子; （ii）选择表达修复的报告分子的细胞，其中报道分子的表达指示所选细胞中存在最佳PTM; 和（iii）鉴定在所选择的细胞中表达的最佳PTM。 另外的报告分子可用于评估特异性和非特异性转拼，以及直接PTM表达。

    TRANSGENIC ANIMAL MODEL FOR SPLICEOSOME-MEDIATED RNA TRANS-SPLICING
    10.
    发明申请
    TRANSGENIC ANIMAL MODEL FOR SPLICEOSOME-MEDIATED RNA TRANS-SPLICING 审中-公开

    公开(公告)号：WO2003093414A3

    公开(公告)日：2003-11-13

    申请号：PCT/US2003/013161

    申请日：2003-04-30

    Applicant: INTRONN, INC. ,  PUTTARAJU, Madaiah ,  MITCHEL, Lloyd ,  ENGELHARDT, John, F. ,  BLANCO, Mariano, Garcia ,  LIU, Xiaoming

    Inventor： PUTTARAJU, Madaiah ,  MITCHEL, Lloyd ,  ENGELHARDT, John, F. ,  BLANCO, Mariano, Garcia ,  LIU, Xiaoming

    IPC: G01N33/00

    Abstract: The present invention relates to development of an animal model system for in vivo testing of spliceosome-mediated RNA trans -splicing reactions. The present invention provides transgenic animals, and methods for generating such animals, that have been genetically engineered to expresses a target precursor messenger RNA molecule (target pre-mRNA) that serves as a substrate for a trans -splicing reaction. Specifically, the transgenic animals contain at least one transgene capable of expressing a target pre-mRNA molecule. The invention provides methods, based on utilization of the transgenic animals, for assessing the specificity and efficiency of a pre- trans -splicing molecule (PTM) designed to interact with a target pre-mRNA and mediate a trans -splicing reaction resulting in the generation of a novel chimeric RNA molecule. The present invention further relates to the transgenic expression of PTM molecules in animals to determine gene function, i.e , functional genetics. The present invention is based on the successful generation of a transgenic animal expressing a target pre-mRNA and, moreover, the use of that animal to detect accurate in vivo trans -splicing reactions in the presence of a PTM.

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