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1. 发明申请

US20100203027A1 VIRAL VECTOR FOR GENE THERAPY 审中-公开
标题翻译：用于基因治疗的病毒载体
公开(公告)号：US20100203027A1
公开(公告)日：2010-08-12
申请号：US12597567
申请日：2008-04-25
申请人： Kenzaburo Tani , Hiroyuki Inoue , Makoto Inoue , Hiroaki Kinoh , Mamoru Hasegawa
发明人： Kenzaburo Tani , Hiroyuki Inoue , Makoto Inoue , Hiroaki Kinoh , Mamoru Hasegawa
IPC分类号： A61K35/12 , C12N15/74 , A61K31/7088 , A61P43/00
CPC分类号： A61K38/195 , A61K38/193 , A61K48/00 , C12N7/00 , C12N15/86 , C12N2710/10343 , C12N2760/18843
摘要： An objective of the present invention is to provide safe viral vectors for gene therapy that can be introduced by a simple technique and sufficiently express genes of interest in vivo. The present inventors demonstrated that anti-tumor effect can be produced when a heparin-binding cytokine such as granulocyte macrophage colony stimulating factor (GM-CSF) and a chemokine such as TARC or RANTES are expressed in vivo using a viral vector based on a negative-strand RNA virus. The present inventors also demonstrated that the protective effect of the vector is superior to that of conventional adenovirus vectors. Thus, the present invention relates to negative-strand RNA viral vectors comprising a cytokine gene and a chemokine gene. The viral vectors are suitable for treatment of cancers, in particular, metastatic cancers. The present invention also provides compositions comprising such viral vectors, and gene therapy methods using them.
摘要翻译：本发明的目的是提供用于基因治疗的安全病毒载体，其可以通过简单的技术引入并充分表达感兴趣的基因。本发明人证明，当使用基于阴性的病毒载体在体内表达肝素结合细胞因子如粒细胞巨噬细胞集落刺激因子（GM-CSF）和趋化因子如TARC或RANTES时可产生抗肿瘤效应品牌RNA病毒。本发明人还证明，载体的保护作用优于常规腺病毒载体。因此，本发明涉及包含细胞因子基因和趋化因子基因的负链RNA病毒载体。病毒载体适合于治疗癌症，特别是转移性癌症。本发明还提供包含这种病毒载体的组合物，以及使用它们的基因治疗方法。

2. 发明申请

US20050221292A1 Vectors with modified protease-dependent tropism 有权
标题翻译：具有修饰的蛋白酶依赖性向量的载体
公开(公告)号：US20050221292A1
公开(公告)日：2005-10-06
申请号：US10513094
申请日：2003-04-30
申请人： Hiroaki Kinoh , Makoto Inoue , Yasuji Ueda , Akihiro Iida , Mamoru Hasegawa , Masanori Kobayashi
发明人： Hiroaki Kinoh , Makoto Inoue , Yasuji Ueda , Akihiro Iida , Mamoru Hasegawa , Masanori Kobayashi
IPC分类号： A61K38/00 , A61K48/00 , A61P35/00 , C07K14/115 , C12N15/45 , C12N15/86 , C12Q1/70 , C12Q1/68
CPC分类号： C07K14/005 , A61K38/00 , A61K48/00 , C07K2319/50 , C12N15/86 , C12N2760/18022 , C12N2760/18822 , C12N2760/18843 , C12N2800/30
摘要： The present invention provides cell fusogenic vectors having replicative ability, whose protease-dependent tropism has been modified. M gene-deficient viral vectors encoding modified F proteins, in which the cleavage site of the F protein of paramyxovirus is modified to be cleaved by different proteases, were produced. In cells transfected with these vectors, the genomic RNA present in the vectors is replicated, and cell fusogenic infection spreads to neighboring cells depending on the presence of other proteases; however, no viral particles are released. The vectors of this invention, encoding the F proteins which are cleaved by proteases whose activity is enhanced in cancer, show cancer growth suppressive effect in vivo.
摘要翻译：本发明提供具有复制能力的细胞融合载体，其蛋白酶依赖性向性已被修饰。产生编码修饰的F蛋白的M基因缺陷型病毒载体，其中修饰了被不同蛋白酶切割的副粘病毒的F蛋白的切割位点。在用这些载体转染的细胞中，载体中存在的基因组RNA被复制，并且根据其它蛋白酶的存在，细胞融合感染扩散到相邻细胞; 然而，没有病毒颗粒被释放。本发明的编码由蛋白酶切割的F蛋白的载体，其活性在癌症中增强，在体内显示出癌症生长抑制作用。

3. 发明申请

US20100297732A1 VECTORS WITH MODIFIED PROTEASE-DEPENDENT TROPISM 审中-公开
标题翻译：具有修饰的蛋白依赖性TROPISM的载体
公开(公告)号：US20100297732A1
公开(公告)日：2010-11-25
申请号：US12712905
申请日：2010-02-25
申请人： Hiroaki KINOH , Makoto Inoue , Yasuji Ueda , Akihiro Iida , Mamoru Hasegawa , Masanori Kobayashi
发明人： Hiroaki KINOH , Makoto Inoue , Yasuji Ueda , Akihiro Iida , Mamoru Hasegawa , Masanori Kobayashi
IPC分类号： C12N7/01 , C12N15/45
CPC分类号： C07K14/005 , A61K38/00 , A61K48/00 , C07K2319/50 , C12N15/86 , C12N2760/18022 , C12N2760/18822 , C12N2760/18843 , C12N2800/30
摘要： The present invention provides cell fusogenic vectors having replicative ability, whose protease-dependent tropism has been modified. M gene-deficient viral vectors encoding modified F proteins, in which the cleavage site of the F protein of paramyxovirus is modified to be cleaved by different proteases, were produced. In cells transfected with these vectors, the genomic RNA present in the vectors is replicated, and cell fusogenic infection spreads to neighboring cells depending on the presence of other proteases; however, no viral particles are released. The vectors of this invention, encoding the F proteins which are cleaved by proteases whose activity is enhanced in cancer, show cancer growth suppressive effect in vivo.
摘要翻译：本发明提供具有复制能力的细胞融合载体，其蛋白酶依赖性向性已被修饰。产生编码修饰的F蛋白的M基因缺陷型病毒载体，其中修饰了被不同蛋白酶切割的副粘病毒的F蛋白的切割位点。在用这些载体转染的细胞中，载体中存在的基因组RNA被复制，并且根据其它蛋白酶的存在，细胞融合感染扩散到相邻细胞; 然而，没有病毒颗粒被释放。本发明的编码由蛋白酶切割的F蛋白的载体，其活性在癌症中增强，在体内显示出癌症生长抑制作用。

4. 发明授权

US07709621B2 Vectors with modified protease-dependent tropism 有权
标题翻译：具有修饰的蛋白酶依赖性向量的载体
公开(公告)号：US07709621B2
公开(公告)日：2010-05-04
申请号：US12140715
申请日：2008-06-17
申请人： Hiroaki Kinoh , Makoto Inoue , Yasuji Ueda , Akihiro Iida , Mamoru Hasegawa , Masanori Kobayashi
发明人： Hiroaki Kinoh , Makoto Inoue , Yasuji Ueda , Akihiro Iida , Mamoru Hasegawa , Masanori Kobayashi
IPC分类号： C07H21/04 , C12N15/45 , C12N7/00 , A61K48/00
CPC分类号： C07K14/005 , A61K38/00 , A61K48/00 , C07K2319/50 , C12N15/86 , C12N2760/18022 , C12N2760/18822 , C12N2760/18843 , C12N2800/30
摘要： The present invention provides cell fusogenic vectors having replicative ability, whose protease-dependent tropism has been modified. M gene-deficient viral vectors encoding modified F proteins, in which the cleavage site of the F protein of paramyxovirus is modified to be cleaved by different proteases, were produced. In cells transfected with these vectors, the genomic RNA present in the vectors is replicated, and cell fusogenic infection spreads to neighboring cells depending on the presence of other proteases; however, no viral particles are released. The vectors of this invention, encoding the F proteins which are cleaved by proteases whose activity is enhanced in cancer, show cancer growth suppressive effect in vivo.
摘要翻译：本发明提供具有复制能力的细胞融合载体，其蛋白酶依赖性向性已被修饰。产生编码修饰的F蛋白的M基因缺陷型病毒载体，其中修饰了被不同蛋白酶切割的副粘病毒的F蛋白的切割位点。在用这些载体转染的细胞中，载体中存在的基因组RNA被复制，并且根据其它蛋白酶的存在，细胞融合感染扩散到相邻细胞; 然而，没有病毒颗粒被释放。本发明的编码由蛋白酶切割的F蛋白的载体，其活性在癌症中增强，在体内显示出癌症生长抑制作用。

5. 发明申请

US20080299642A1 VECTORS WITH MODIFIED PROTEASE-DEPENDENT TROPISM 有权
标题翻译：具有修饰的蛋白依赖性TROPISM的载体
公开(公告)号：US20080299642A1
公开(公告)日：2008-12-04
申请号：US12140715
申请日：2008-06-17
申请人： Hiroaki Kinoh , Makoto Inoue , Yasuji Ueda , Akihiro Iida , Mamoru Hasegawa , Masanori Kobayashi
发明人： Hiroaki Kinoh , Makoto Inoue , Yasuji Ueda , Akihiro Iida , Mamoru Hasegawa , Masanori Kobayashi
IPC分类号： C12N7/01 , C07H21/04 , C12N15/63
CPC分类号： C07K14/005 , A61K38/00 , A61K48/00 , C07K2319/50 , C12N15/86 , C12N2760/18022 , C12N2760/18822 , C12N2760/18843 , C12N2800/30
摘要： The present invention provides cell fusogenic vectors having replicative ability, whose protease-dependent tropism has been modified. M gene-deficient viral vectors encoding modified F proteins, in which the cleavage site of the F protein of paramyxovirus is modified to be cleaved by different proteases, were produced. In cells transfected with these vectors, the genomic RNA present in the vectors is replicated, and cell fusogenic infection spreads to neighboring cells depending on the presence of other proteases; however, no viral particles are released. The vectors of this invention, encoding the F proteins which are cleaved by proteases whose activity is enhanced in cancer, show cancer growth suppressive effect in vivo.
摘要翻译：本发明提供具有复制能力的细胞融合载体，其蛋白酶依赖性向性已被修饰。产生编码修饰的F蛋白的M基因缺陷型病毒载体，其中修饰了被不同蛋白酶切割的副粘病毒的F蛋白的切割位点。在用这些载体转染的细胞中，载体中存在的基因组RNA被复制，并且根据其它蛋白酶的存在，细胞融合感染扩散到相邻细胞; 然而，没有病毒颗粒被释放。本发明的编码由蛋白酶切割的F蛋白的载体，其活性在癌症中增强，在体内显示出癌症生长抑制作用。

6. 发明授权

US07402427B2 Vectors with modified protease-dependent tropism 有权
标题翻译：具有修饰的蛋白酶依赖性向量的载体
公开(公告)号：US07402427B2
公开(公告)日：2008-07-22
申请号：US10513094
申请日：2003-04-30
申请人： Hiroaki Kinoh , Makoto Inoue , Yasuji Ueda , Akihiro Iida , Mamoru Hasegawa , Masanori Kobayashi
发明人： Hiroaki Kinoh , Makoto Inoue , Yasuji Ueda , Akihiro Iida , Mamoru Hasegawa , Masanori Kobayashi
IPC分类号： C12N15/86 , A01N63/00 , A61K39/155
CPC分类号： C07K14/005 , A61K38/00 , A61K48/00 , C07K2319/50 , C12N15/86 , C12N2760/18022 , C12N2760/18822 , C12N2760/18843 , C12N2800/30
摘要： The present invention provides cell fusogenic vectors having replicative ability, whose protease-dependent tropism has been modified. M gene-deficient viral vectors encoding modified F proteins, in which the cleavage site of the F protein of paramyxovirus is modified to be cleaved by different proteases, were produced. In cells transfected with these vectors, the genomic RNA present in the vectors is replicated, and cell fusogenic infection spreads to neighboring cells depending on the presence of other proteases; however, no viral particles are released. The vectors of this invention, encoding the F proteins which are cleaved by proteases whose activity is enhanced in cancer, show cancer growth suppressive effect in vivo.
摘要翻译：本发明提供具有复制能力的细胞融合载体，其蛋白酶依赖性向性已被修饰。产生编码修饰的F蛋白的M基因缺陷型病毒载体，其中修饰了被不同蛋白酶切割的副粘病毒的F蛋白的切割位点。在用这些载体转染的细胞中，载体中存在的基因组RNA被复制，并且根据其它蛋白酶的存在，细胞融合感染扩散到相邻细胞; 然而，没有病毒颗粒被释放。本发明的编码由蛋白酶切割的F蛋白的载体，其活性在癌症中增强，在体内显示出癌症生长抑制作用。

7. 发明授权

US07144579B2 Paramyxoviruses comprising modified transcription start sequence 失效
标题翻译：副粘病毒包括修饰的转录起始序列
公开(公告)号：US07144579B2
公开(公告)日：2006-12-05
申请号：US09979908
申请日：2001-11-28
申请人： Yoshiyuki Nagai , Atsushi Kato , Mamoru Hasegawa , Makoto Inoue
发明人： Yoshiyuki Nagai , Atsushi Kato , Mamoru Hasegawa , Makoto Inoue
IPC分类号： C07H19/00 , C12N15/63 , C12N15/66 , A61K39/12 , A61K39/155
CPC分类号： C07K14/005 , A61K48/00 , C12N15/86 , C12N2760/18822 , C12N2760/18843
摘要： The present invention provides virus vectors of the family Paramyxoviridae in which the transcription start (S) sequence has been modified so as to modify the expression of genes located downstream thereof, a method for producing the vectors, and uses thereof. By measuring the transcription initiation efficiency of the S sequence of each gene carried by Sendai viruses (SeV), it was clarified that the S sequence of F gene has a significantly lower ability to promote transcription than the other three S sequences. When the S sequence of the F gene of wild type Sendai virus was substituted by the S sequence of the P/M/HN gene-type showing a high transcription initiation efficiency, the F gene of the resultant Sendai virus mutant and genes located downstream thereof show elevated expression levels. It was also revealed that this mutant proliferates more quickly than the wild type. The vectors of this invention are useful in elevating the expression of foreign genes and producing pharmaceutical compositions and vaccines. Furthermore, by lowering virus gene expression from virus vectors, it is possible to suppress transcription and/or replication and reduce cytotoxicity of the vector genome.
摘要翻译：本发明提供了副粘病毒科的病毒载体，其中已经修饰了转录起始（S）序列，以便修饰其下游的基因的表达，生成载体的方法及其用途。通过测量仙台病毒（SeV）携带的每个基因的S序列的转录起始效率，阐明了F基因的S序列比其他三个S序列具有显着较低的促进转录能力。当野生型仙台病毒的F基因的S序列被显示高转录起始效率的P / M / HN基因型的S序列取代时，得到的仙台病毒突变体的F基因和位于其下游的基因显示升高的表达水平。还显示，该突变体比野生型增殖更快。本发明的载体可用于提高外源基因的表达并产生药物组合物和疫苗。此外，通过降低来自病毒载体的病毒基因表达，可以抑制转录和/或复制并降低载体基因组的细胞毒性。

8. 发明授权

US08283163B2 Method for production of dendritic cell 有权
标题翻译：树突状细胞的生产方法
公开(公告)号：US08283163B2
公开(公告)日：2012-10-09
申请号：US12600103
申请日：2008-05-12
申请人： Makoto Inoue , Mamoru Hasegawa , Yoshikazu Yonemitsu , Yui Harada
发明人： Makoto Inoue , Mamoru Hasegawa , Yoshikazu Yonemitsu , Yui Harada
IPC分类号： C12N5/071 , C12N5/02
CPC分类号： C12N5/0639 , C12N2501/125 , C12N2501/22 , C12N2501/23 , C12N2501/26
摘要： The present invention provides methods for producing DCs, which comprise the step of culturing DC precursor cells in the presence of multiple cytokines, dendritic cells produced thereby, and uses thereof. The methods of the present invention enable production of large quantities of DC precursors with a high ability to differentiate into DCs. The present invention enables one to obtain large quantities of DCs from a small number of DC precursor cells, and therefore makes it easier to increase the number of DCs for administration in DC-based anti-tumor immunotherapy, treatment of infection, and such. Thus, an enhancement is expected for the effect of DC vaccines.
摘要翻译：本发明提供了生产DC的方法，其包括在多种细胞因子存在下培养DC前体细胞的步骤，由此产生的树突状细胞及其用途。本发明的方法能够生产具有高分化成DC的能力的大量DC前体。本发明能够从少量的DC前体细胞获得大量的DC，因此能够更容易地增加DC-基抗肿瘤免疫治疗中的DC给药次数，感染治疗等。因此，预期DC疫苗的效果将得到改善。

9. 发明申请

US20100184214A1 METHOD FOR PRODUCTION OF DENDRITIC CELL 有权
标题翻译：生产细胞的方法
公开(公告)号：US20100184214A1
公开(公告)日：2010-07-22
申请号：US12600103
申请日：2008-05-12
申请人： Makoto Inoue , Mamoru Hasegawa , Yoshikazu Yonemitsu , Yui Harada
发明人： Makoto Inoue , Mamoru Hasegawa , Yoshikazu Yonemitsu , Yui Harada
IPC分类号： C12N5/071 , C12N5/02
CPC分类号： C12N5/0639 , C12N2501/125 , C12N2501/22 , C12N2501/23 , C12N2501/26
摘要： The present invention provides methods for producing DCs, which comprise the step of culturing DC precursor cells in the presence of multiple cytokines, dendritic cells produced thereby, and uses thereof. The methods of the present invention enable production of large quantities of DC precursors with a high ability to differentiate into DCs. The present invention enables one to obtain large quantities of DCs from a small number of DC precursor cells, and therefore makes it easier to increase the number of DCs for administration in DC-based anti-tumor immunotherapy, treatment of infection, and such. Thus, an enhancement is expected for the effect of DC vaccines.
摘要翻译：本发明提供了生产DC的方法，其包括在多种细胞因子存在下培养DC前体细胞的步骤，由此产生的树突状细胞及其用途。本发明的方法能够生产具有高分化成DC的能力的大量DC前体。本发明能够从少量的DC前体细胞获得大量的DC，因此能够更容易地增加DC-基抗肿瘤免疫治疗中的DC给药次数，感染治疗等。因此，预期DC疫苗的效果将得到改善。

10. 发明申请

US20090162320A1 GENE TRANSFER INTO AIRWAY EPITHELIAL STEM CELL BY USING LENTIVIRAL VECTOR PSEUDOTYPED WITH RNA VIRUS OR DNA VIRUS SPIKE PROTEIN 审中-公开
标题翻译：通过使用用RNA病毒或DNA病毒SPIKE蛋白质刺激的宿主细胞将基因转移到空中上皮细胞中
公开(公告)号：US20090162320A1
公开(公告)日：2009-06-25
申请号：US12091646
申请日：2006-10-27
申请人： Katsuyuki Mitomo , Makoto Inoue , Hitoshi Iwasaki , Mamoru Hasegawa
发明人： Katsuyuki Mitomo , Makoto Inoue , Hitoshi Iwasaki , Mamoru Hasegawa
IPC分类号： C12N15/86 , C12N5/10 , A61K48/00 , A61P11/00
CPC分类号： C12N15/86 , A61K9/0043 , A61K38/162 , A61K38/1709 , A61K38/177 , A61K48/00 , C07K14/4712 , C12N5/0688 , C12N7/00 , C12N2510/00 , C12N2740/15033 , C12N2740/15043 , C12N2740/15045 , C12N2810/6072 , C12N2810/609
摘要： The present inventors successfully introduced genes into stem cells of airway epithelial tissues using simian immunodeficiency virus vectors pseudotyped with F and HN, which are envelope glycoproteins of Sendai virus. Gene transfer into airway epithelial tissue stem cells using a vector of the present invention is useful for gene therapy of genetic respiratory diseases such as cystic fibrosis. Furthermore, it is possible to select respiratory organs such as the lungs as production tissues for providing proteins that are deficient due to genetic diseases.
摘要翻译：本发明人成功地将基因引入气道上皮组织的干细胞，其中使用以F和HN为假型的猿免疫缺陷病毒载体，其是仙台病毒的包膜糖蛋白。使用本发明的载体将基因转移到气道上皮组织干细胞中可用于遗传呼吸系统疾病如囊性纤维化的基因治疗。此外，可以选择诸如肺的呼吸器官作为用于提供由于遗传疾病而缺陷的蛋白质的生产组织。

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