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1. 发明公开

EP3377116A1 COMPOSITIONS AND METHODS FOR CORRECTION OF HERITABLE OCULAR DISEASE 审中-实审
公开(公告)号：EP3377116A1
公开(公告)日：2018-09-26
申请号：EP16867296.2
申请日：2016-11-18
申请人： The Trustees of The University of Pennsylvania , Mitchell, Lloyd G.
发明人： MITCHELL, Lloyd, G. , BENNETT, Jean , BENNICELLI, Jeannette , DOOLEY, Scott, J.
IPC分类号： A61K48/00 , C07H21/02 , C07H21/04
CPC分类号： C12N15/86 , A61K48/005 , C12N15/00 , C12N2740/10043 , C12N2750/14143
摘要： A nucleic acid trans-splicing molecule is provided that can replace an exon in a targeted mammalian ocular gene carrying a defect or mutation causing an ocular disease with an exon having the naturally-occurring sequence without the defect or mutation. A method of treating an ocular disease, e.g., Stargardt's Disease, caused by a defect or mutation in a target gene, e.g., ABCA4 comprising: administering to the ocular cells of a subject having an ocular disease a composition comprising a recombinant AAV comprising a nucleic acid trans-splicing molecule as described above.

2. 发明申请

WO2005070023A2 EXPRESSION OF APOA-1 AND VARIANTS THEREOF USING SPLICEOSOME MEDIATED RNA TRANS-SPLICING 审中-公开
标题翻译： APOA-1的表达及其使用SPLICEOSOME介导的RNA转移分离的变体
公开(公告)号：WO2005070023A2
公开(公告)日：2005-08-04
申请号：PCT/US2005002392
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： C07K14/775 , C12N15/11 , C12N15/113
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.
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，其导致apoA-1变体（本文中称为apoA-1 Milano变体）的优选实施方案的表达。本发明的组合物包括被设计成与靶前体信使RNA分子（靶前mRNA）相互作用并且介导导致产生新的嵌合RNA分子（嵌合体）的反式剪接反应的预转录分子（PTM） RNA）能够编码apoA-1 Milano变体。该变体蛋白质的表达导致保护免受斑块积聚引起的血管疾病，即中风和心脏病发作。特别地，预发明的PTM包括经遗传工程改造以与apoA-1靶preRNA相互作用以产生载脂蛋白-A 1米兰变体的表达的那些。此外，本发明的PTM包括经遗传工程改造以与载脂蛋白B或白蛋白或其它特异性靶前体mRNA相互作用以产生apoB / apoA-1和/或alb / apoA-1野生型或米诺融合蛋白从而降低apoB表达并同时产生ApoA-1功能。

3. 发明申请

WO03003014A9 METHODS AND COMPOSITIONS FOR DETERMINING THE PURITY OF AND PURIFYING CHEMICALLY SYNTHESIZED NUCLEIC ACIDS 审中-公开
标题翻译：用于测定和纯化化学合成核酸的方法和组合物
公开(公告)号：WO03003014A9
公开(公告)日：2004-05-13
申请号：PCT/US0220418
申请日：2002-06-28
申请人： VERI Q INC , PROTEOME SCIENCES PLC , PEARCE CHRISTOPHER D J , MITCHELL LLOYD G
发明人： PEARCE CHRISTOPHER D J , MITCHELL LLOYD G
IPC分类号： C07K16/44 , C12M1/00 , C12M1/34 , C12N15/09 , C12P19/34 , C12Q1/68 , C40B40/06 , C40B50/14 , G01N33/53 , G01N33/543 , G01N33/566 , G01N33/58 , G01N37/00 , C07H21/00 , C07H21/02 , C07H21/04
CPC分类号： B82Y30/00 , B01J2219/00608 , B01J2219/0061 , B01J2219/00612 , B01J2219/00621 , B01J2219/00626 , B01J2219/0063 , B01J2219/00637 , B01J2219/00641 , B01J2219/00659 , B01J2219/00675 , B01J2219/00693 , B01J2219/00722 , C07K16/44 , C12P19/34 , C12Q1/6804 , C12Q1/6837 , C40B40/06 , C40B50/14 , G01N33/5308 , G01N33/543 , G01N2500/00 , Y02P20/55 , C12Q2565/531 , C12Q2563/131
摘要： An antibody microarray is described comprising a plurality of antibodies immobilized on a substrate, wherein each antibody specifically binds to a synthetic oligomer (e.g., an oligonucleotide or oligopeptide) having an organic protecting group covalently bound thereto, which antibody does not bind to that synthetic oligomer when the organic protecting group is not covalently bound thereto. Methods of making and using such antibodies are disclosed, along with cells for making such antibodies. Methods of making and using such antibody microarrays are also disclosed.
摘要翻译：描述了抗体微阵列，其包含固定在底物上的多种抗体，其中每种抗体特异性结合具有与其共价结合的有机保护基的合成低聚物（例如，寡核苷酸或寡肽），该抗体不与该合成寡聚物结合当有机保护基团不共价结合时。公开了制备和使用这些抗体的方法以及用于制备这种抗体的细胞。还公开了制备和使用这种抗体微阵列的方法。

4. 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.

5. 发明申请

WO2004006678A1 SPLICEOSOME MEDIATED RNA TRANS-SPLICING FOR CORRECTION OF SKIN DISORDERS 审中-公开
标题翻译： SPLICEOSOME MEDIATED RNA TRANS-SPLICING FOR Corrients of Skine Disorders
公开(公告)号：WO2004006678A1
公开(公告)日：2004-01-22
申请号：PCT/US2003/022469
申请日：2003-07-17
申请人： INTRONN, INC. , MITCHELL, Lloyd, G. , PUTTARAJU, Madaiah , DALLINGER, Guenter , KLAUSEGGER, Alfred , BAUER, Johann
发明人： MITCHELL, Lloyd, G. , PUTTARAJU, Madaiah , DALLINGER, Guenter , KLAUSEGGER, Alfred , BAUER, Johann
IPC分类号： A01N47/40
CPC分类号： C12N15/113 , A61K48/00 , C07H21/02 , C07H21/04 , C12N2510/00
摘要： The present invention provides methods and compositions for generating novel nucleic acid molecules through targeted spliceosomal mediated RNA traps-splicing. The compositions of the invention include pre-traps-splicing molecules (PTMs) designed to interact with a target precursor messenger RNA molecule (target pre-mRNA) and mediate a traps-splicing reaction resulting in the generation of a novel chimeric RNA molecule (chimeric RNA). In particular, the PTMs of the present invention can be genetically engineered to interact with a specific target premRNA expressed in cells of the skin so as to result in correction of genetic defects responsible for a variety of different skin disorders to encode a reporter molecule or protein that may have therapeutic value. The compositions of the invention further include recombinant vectors 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 specific target pre-Mrna expressed within cells of the skin under conditions in which a portion of the PTM is traps-spliced to a portion of the target pre-mRNA to form a chimeric RNA molecule wherein the genetic defect in the specific gene has been corrected. The present invention is based on the successful trans -splicing of the collagen XVII pre-mRNA thereby establishing the usefulness of trans -splicing for correction of skin specific genetic defects. The methods and compositions of the present invention can be used in gene therapy for treatment of specific disorders of the skin, i.e ., genodermatoses, such as epidermal fragility disorders, keratinization disorders, hair disorders and pigmentation disorders as well as cancers of the skin.
摘要翻译：本发明提供了通过靶向剪接体介导的RNA捕获 - 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靶前体信使RNA分子（靶前体mRNA）相互作用的诱捕前剪接分子（PTM），并介导产生新型嵌合RNA分子的陷阱剪接反应（嵌合 RNA）。特别地，本发明的PTM可以进行遗传工程改造以与皮肤细胞中表达的特异性靶基因前体RNA相互作用，从而导致对多种不同皮肤病症负责编码报告分子或蛋白质的遗传缺陷的校正这可能有治疗价值。本发明的组合物还包括能够表达本发明的PTM和表达所述PTM的细胞的重组载体系统。本发明的方法包括使本发明的PTM与在皮肤细胞内表达的特异性靶前Mrna接触，其中一部分PTM被剪接到目标前mRNA的一部分以形成嵌合体其中特异性基因的遗传缺陷已被校正的RNA分子。本发明基于胶原XVII前体mRNA的成功的转拼，从而确定了用于修复皮肤特异性遗传缺陷的转拼的有用性。本发明的方法和组合物可用于治疗皮肤特异性病症的基因疗法，即皮肤病，如表皮脆性障碍，角质化病症，毛发病症和色素沉着病以及皮肤癌。

6. 发明申请

WO2003104416A3 SPLICEOSOME MEDIATED RNA TRANS-SPLICING IN STEM CELLS 审中-公开
公开(公告)号：WO2003104416A3
公开(公告)日：2003-12-18
申请号：PCT/US2003/017954
申请日：2003-06-05
申请人： INTRONN, INC. , MITCHELL, Lloyd, G. , ENGLEHARDT, John , LIU, Xiao, Ming
发明人： MITCHELL, Lloyd, G. , ENGLEHARDT, John , LIU, Xiao, Ming
IPC分类号： C12P19/34
摘要： The present invention provides methods and compositions for generating novel nucleic acid molecules through targeted spliceosomal mediated trans -splicing in stem cells. The compositions of the invention include stem cells engineered to express 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 novel chimeric RNA molecules (chimeric RNA). In particular, the stem cells of the present invention are genetically engineered to express a PTM that will interact with a specific target pre-mRNA expressed within a stem cell as it differentiates so as to result in correction of a genetic defect responsible for a genetic disorder. The methods of the invention encompass transferring a nucleic acid molecule capable of encoding a PTM of interest into a stem cell followed by transplantation of the PTM modified stem cell into a host. As the stem cell differentiates the target pre-mRNA is expressed thereby providing the substrate for a trans -splicing reaction. The present invention is based on the successful transfer and expression of a nucleic acid molecule encoding a PTM capable of interacting with a cystic fibrosis transmembrane conductance regulator (CFTR) pre-mRNA into primary human surface airway progenitor cells. The methods and compositions of the present invention can be used to correct genetic defects associated with a variety of different disorders such as cystic fibrosis, hemophilia, sickle cell anemia, Tay-Sachs disease, thalassemias, polycystic kidney disease and muscular dystrophy, to name a few.

7. 发明申请

WO2003104412A2 SPLICEOSOME MEDIATED RNA TRANS-SPLICING AND CORRECTION OF FACTOR VIII GENETIC DEFECTS USING SPLICEOSOME MEDIATED RNA TRANS SPLING 审中-公开
标题翻译： SPLICEOSOME介导的RNA转移分离和因子VIII的遗传缺陷的修正使用SPLICEOSOME介导的RNA转移分离
公开(公告)号：WO2003104412A2
公开(公告)日：2003-12-18
申请号：PCT/US2003/017913
申请日：2003-06-05
申请人： INTRONN, INC. , MITCHELL, Lloyd, G. , MANSFIELD, S. Gary , PUTTARAJU, Madaiah , CLARK, Rebecca , GARCIA-BLANCO, Mariano, A.
发明人： MITCHELL, Lloyd, G. , MANSFIELD, S. Gary , PUTTARAJU, Madaiah , CLARK, Rebecca , GARCIA-BLANCO, Mariano, A.
IPC分类号： C12N
CPC分类号： C07K14/755 , C12N15/10
摘要： 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.
摘要翻译：本发明的组合物包括被设计为与靶前体信使RNA分子（靶前mRNA）相互作用并且介导导致产生新的嵌合RNA分子（嵌合体）的反式剪接反应的预转录分子（PTM） RNA）。特别地，本发明的PTM被遗传工程化以与因子VIII（FVIII）靶前mRNA相互作用，从而导致血友病A引起的凝血FVIII遗传缺陷的校正。本发明的组合物还包括重组载体系统能够表达本发明的PTM和表达所述PTM的细胞。本发明的方法包括将本发明的PTM与FVIII靶前体mRNA接触，其中将部分PTM转染到靶前mRNA的一部分以形成RNA分子的条件下，其中遗传缺陷在FVIII基因中已被纠正。本发明的方法和组合物可用于基因治疗中用于校正FVIII病症如血友病A.

8. 发明申请

WO2003003014A1 METHODS AND COMPOSITIONS FOR DETERMINING THE PURITY OF AND PURIFYING CHEMICALLY SYNTHESIZED NUCLEIC ACIDS 审中-公开
标题翻译：用于测定和纯化化学合成核酸的方法和组合物
公开(公告)号：WO2003003014A1
公开(公告)日：2003-01-09
申请号：PCT/US2002/020418
申请日：2002-06-28
申请人： VERI-Q, INC. , PEARCE, Christopher, D., J. , MITCHELL, Lloyd, G.
发明人： PEARCE, Christopher, D., J. , MITCHELL, Lloyd, G.
IPC分类号： G01N33/543
CPC分类号： B82Y30/00 , B01J2219/00608 , B01J2219/0061 , B01J2219/00612 , B01J2219/00621 , B01J2219/00626 , B01J2219/0063 , B01J2219/00637 , B01J2219/00641 , B01J2219/00659 , B01J2219/00675 , B01J2219/00693 , B01J2219/00722 , C07K16/44 , C12P19/34 , C12Q1/6804 , C12Q1/6837 , C40B40/06 , C40B50/14 , G01N33/5308 , G01N33/543 , G01N2500/00 , Y02P20/55 , C12Q2565/531 , C12Q2563/131
摘要： An antibody microarray is described comprising a plurality of antibodies immobilized on a substrate, wherein each antibody specifically binds to a synthetic oligomer (e.g., an oligonucleotide or oligopeptide) having an organic protecting group covalently bound thereto, which antibody does not bind to that synthetic oligomer when the organic protecting group is not covalently bound thereto. Methods of making and using such antibodies are disclosed, along with cells for making such antibodies. Methods of making and using such antibody microarrays are also disclosed.
摘要翻译：描述了抗体微阵列，其包含固定在底物上的多种抗体，其中每种抗体特异性结合具有与其共价结合的有机保护基的合成低聚物（例如，寡核苷酸或寡肽），该抗体不与该合成寡聚物结合当有机保护基团不共价结合时。公开了制备和使用这些抗体的方法以及用于制备这种抗体的细胞。还公开了制备和使用这种抗体微阵列的方法。

9. 发明申请

WO2006026611A3 REVERSE TRANSCRIPTASE MEDIATED RNA GENE EXPRESSION 审中-公开
标题翻译：逆转录酶介导的RNA基因表达
公开(公告)号：WO2006026611A3
公开(公告)日：2009-04-16
申请号：PCT/US2005030825
申请日：2005-08-30
申请人： MITCHELL LLOYD G
发明人： MITCHELL LLOYD G
IPC分类号： C12Q1/00 , C12Q1/68 , C12Q1/70
CPC分类号： C12N9/1276
摘要： The present invention provides methods and compositions for expressing a polypeptide or nucleic acid of interest in cells expressing reverse transcriptase (RT). The compositions of the invention include reverse transcriptase RNA (RTD-RNA) molecules that are designed to be reverse transcribed into a DNA molecule capable of encoding a polypeptide or nucleic acid of interest. Polypeptides of interest include cytotoxic, therapeutic, enzymatic, or reporter polypeptides. Nucleic acid molecules of interest include those capable of regulating, altering or reprogramming gene expression, for example, those capable of functioning as antisense, aptamer, decoy, inhibitor, ribozyme, or RNAi molecules.
摘要翻译：本发明提供用于在表达逆转录酶（RT）的细胞中表达感兴趣的多肽或核酸的方法和组合物。本发明的组合物包括逆转录酶RNA（RTD-RNA）分子，其被设计为逆转录成能够编码感兴趣的多肽或核酸的DNA分子。感兴趣的多肽包括细胞毒性，治疗性，酶学或报道多肽。感兴趣的核酸分子包括能够调节，改变或重编程基因表达的核酸分子，例如能够作为反义，适体，诱饵，抑制剂，核酶或RNAi分子起作用的核酸分子。

10. 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.

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