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1. 发明申请

WO2005070948A1 CORRECTION OF ALPHA-1-ANTITRYPSIN GENETIC DEFECTS USING SPLICEOSOME MEDIATED RNA TRANS SPLICING 审中-公开
标题翻译：使用SPLICEOSOME介导的RNA转移分离的ALPHA-1-抗体基因缺陷的修正
公开(公告)号：WO2005070948A1
公开(公告)日：2005-08-04
申请号：PCT/US2005/002549
申请日：2005-01-21
申请人： INTRONN, INC. , PUTTARAJU, Madaiah , OTTO, Edward , GARCIA-BLANCO, Mariano, A. , MCGARRITY, Gerard, J. , TEMPLE, Gary, F. , COTE, Collette , MITCHELL, Lloyd, G. , MANSFIELD, Gary, S.
发明人： PUTTARAJU, Madaiah , OTTO, Edward , GARCIA-BLANCO, Mariano, A. , MCGARRITY, Gerard, J. , TEMPLE, Gary, F. , COTE, Collette , MITCHELL, Lloyd, G. , MANSFIELD, Gary, S.
IPC分类号： C07H21/02
CPC分类号： C12N15/10 , C12N15/102 , C12P19/34
摘要： The present invention provides methods and compositions for generating novel nucleic acid molecules through targeted spliceosomal mediated RNA trans -splicing. The compositions of the invention include pre-trans -splicing molecules (PTMs) designed to interact with a SERPINAI 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 include those genetically engineered to interact with SERPINA1 target pre-mRNA so as to result in correction of SERPINAI genetic defects responsible for AAT deficiency. The PTMs of the invention may also comprise sequences that are processed out of the PTM to yield duplex siRNA molecules directed specifically to mutant SERPIN Al mRNAs. Such duplexed siRNAs are designed to reduce the accumulation of toxic AAT protein in liver cells. The methods and compositions of the present invention can be used in gene therapy for correction of SERPINAI disorders such as AAT deficiency.
摘要翻译：本发明提供了通过靶向剪接体介导的RNA转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为与SERPINAI靶前体信使RNA分子（靶前体mRNA）相互作用的转录前分子（PTM），并介导导致产生新型嵌合RNA分子的反式剪接反应（嵌合RNA）。特别地，本发明的PTM包括经遗传工程改造以与SERPINA1靶前体mRNA相互作用，从而导致对负责AAT缺陷的SERPINAI遗传缺陷的校正。本发明的PTM还可以包含从PTM中加工得到的特异性引导突变体SERPIN A1 mRNA的双链体siRNA分子的序列。这样的双链体siRNA被设计为减少肝细胞中有毒的AAT蛋白的积累。本发明的方法和组合物可用于基因治疗以纠正SERPINAI病症如AAT缺陷。

2. 发明申请

WO2004038380A3 SCREENING METHODS FOR IDENTIFICATION OF EFFICIENT PRE-TRANS-SPLICING MOLECULES 审中-公开
公开(公告)号：WO2004038380A3
公开(公告)日：2004-05-06
申请号：PCT/US2003/034102
申请日：2003-10-23
申请人： INTRONN, INC. , MITCHELL, Lloyd, G. , PUTTARAJU, Madaiah , GARCIA-BLANCO, Mariano , OTTO, Edward , YANG, Yanping
发明人： MITCHELL, Lloyd, G. , PUTTARAJU, Madaiah , GARCIA-BLANCO, Mariano , OTTO, Edward , YANG, Yanping
IPC分类号： C12Q1/68
摘要： 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.

3. 发明申请

WO2005023990A3 TRANS-SPLICING MEDIATED PHOTODYNAMIC THERAPY 审中-公开
公开(公告)号：WO2005023990A3
公开(公告)日：2005-03-17
申请号：PCT/US2004/029022
申请日：2004-09-07
申请人： INTRONN, INC. , MITCHELL, Lloyd, G. , OTTO, Edward , MERRIL, Carl, R.
发明人： MITCHELL, Lloyd, G. , OTTO, Edward , MERRIL, Carl, R.
IPC分类号： A61K48/00
摘要： The present invention provides methods and compositions for conferring selective death on cells expressing a specific target precursor messenger RNA (selective target pre-mRNA). The compositions of the invention include pre-trans-splicing molecules (PTMs) designed to interact with a target precursor messenger RNA molecule (target pre-mRMA) expressed within a cell and mediate a trans-splicing reaction resulting in the generation of a novel chimeric mRNA molecule (chimeric mRNA) capable of encoding a light producing protein or enzyme. Cell death is further mediated by the presence of a photosensitizer which upon photoactivation produces cytotoxicity.

4. 发明公开

EP1716165A2 EXPRESSION OF APOA-1 AND VARIANTS THEREOF USING SPLICEOSOME MEDIATED RNA TRANS - SPLICING 审中-公开
标题翻译：载脂蛋白A-1的表达及其变体使用剪接体介导的RNA反式剪接
公开(公告)号：EP1716165A2
公开(公告)日：2006-11-02
申请号：EP05722539.3
申请日：2005-01-21
申请人： Intronn, Inc.
发明人： PUTTARAJU, Madaiah , OTTO, Edward , GARCIA-BLANCO, Mariano, A. , MCGARRITY, Gerard, J. , TEMPLE, Gary, F. , MITCHELL, Lloyd, G.
IPC分类号： C07H21/02 , C12N5/10 , C12N15/09 , C12P19/34
CPC分类号： C07K14/775 , C12N15/111 , C12N15/113 , C12N2310/11 , C12N2310/3519 , C12N2320/33
摘要： 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.

5. 发明公开

EP1579004A2 SCREENING METHODS FOR IDENTIFICATION OF EFFICIENT PRE-TRANS-SPLICING MOLECULES 有权
标题翻译：筛选方法，确定有效的PRE-TRANS-SPLEISSMOLEKÜLE
公开(公告)号：EP1579004A2
公开(公告)日：2005-09-28
申请号：EP03779324.7
申请日：2003-10-23
申请人： Intronn, Inc.
发明人： MITCHELL, Lloyd, G. , PUTTARAJU, Madaiah , GARCIA-BLANCO, Mariano , OTTO, Edward , YANG, Yanping
IPC分类号： C12Q1/68
CPC分类号： C12N15/1027 , C12N15/1086 , G01N33/5023
摘要： 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.

6. 发明申请

WO2005070023A3 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
申请人： INTRONN, INC. , PUTTARAJU, Madaiah , OTTO, Edward , GARCIA-BLANCO, Mariano, A. , MCGARRITY, Gerard, J. , TEMPLE, Gary, F. , MITCHELL, Lloyd, G.
发明人： PUTTARAJU, Madaiah , OTTO, Edward , GARCIA-BLANCO, Mariano, A. , MCGARRITY, Gerard, J. , TEMPLE, Gary, F. , MITCHELL, Lloyd, G.
IPC分类号： C07H21/02
摘要： 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.

7. 发明申请

WO2004050680A3 USE OF SPLICEOSOME MEDIATED RNA TRANS-SPLICING TO CONFER CELL SELECTIVE REPLICATION TO ADENOVIRUSES 审中-公开
公开(公告)号：WO2004050680A3
公开(公告)日：2004-06-17
申请号：PCT/US2003/014804
申请日：2003-05-08
申请人： INTRONN, INC.
发明人： OTTO, Edward
IPC分类号： C07H21/00
摘要： The present invention provides methods and compositions for conferring tumor selective cell death on cancer cells expressing specific target precursor messenger RNA molecules (cancer cell selective target pre-mRNAs). The compositions of the invention include conditionally replicative adenoviruses that have been genetically engineered to express one or more pre- trans -splicing molecules (PTMs) designed to interact with one or more cancer cell target pre-mRNA and mediate a trans -splicing reaction resulting in the generation of novel chimeric RNA molecules (chimeric RNA) capable of encoding adenovirus specific protein(s). Adenovirus specific proteins include those proteins complementing an essential activity necessary for replication of a defective adenovirus. The methods and compositions of the invention may be used to target a lytic adenovirus infection to cancer cells thereby providing a method for selective destruction of cancer cells. In addition, the adenoviruses of the invention may be engineered to encode PTMs designed to interact with target pre-mRNAs encoded by infectious agents within a cell, thereby targeting selective destruction of cells infected with such agents.

8. 发明公开

EP1504016A2 USE OF SPLICEOSOME MEDIATED RNA TRANS-SPLICING TO CONFER CELL SELECTIVE REPLICATION TO ADENOVIRUSES 审中-公开
标题翻译： USE剪接体介导的RNA反式剪接，以腺病毒细胞选择REPLICATION贷款
公开(公告)号：EP1504016A2
公开(公告)日：2005-02-09
申请号：EP03810034.3
申请日：2003-05-08
申请人： Intronn, Inc.
发明人： OTTO, Edward
IPC分类号： C07H21/00 , C07H21/02 , C07H21/04 , A01N63/00 , A61K48/00
CPC分类号： C12N15/86 , A61K48/00 , C12N2710/10343 , C12N2710/10345 , C12N2840/445
摘要： The present invention provides methods and compositions for conferring tumor selective cell death on cancer cells expressing specific target precursor messenger RNA molecules (cancer cell selective target pre-mRNAs). The compositions of the invention include conditionally replicative adenoviruses that have been genetically engineered to express one or more pre-trans-splicing molecules (PTMs) designed to interact with one or more cancer cell target pre-mRNA and mediate a trans-splicing reaction resulting in the generation of novel chimeric RNA molecules (chimeric RNA) capable of encoding adenovirus specific protein(s). Adenovirus specific proteins include those proteins complementing an essential activity necessary for replication of a defective adenovirus. The methods and compositions of the invention may be used to target a lytic adenovirus infection to cancer cells thereby providing a method for selective destruction of cancer cells. In addition, the adenoviruses of the invention may be engineered to encode PTMs designed to interact with target pre-mRNAs encoded by infectious agents within a cell, thereby targeting selective destruction of cells infected with such agents.

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