公开(公告)号：US20090170798A1

公开(公告)日：2009-07-02

申请号：US11918862

申请日：2006-04-20

申请人： Hideo Hara ,  Takeshi Tabira ,  Yoshikazu Yonemitsu ,  Makoto Inoue ,  Yumiko Tokusumi ,  Mamoru Hasegawa

发明人： Hideo Hara ,  Takeshi Tabira ,  Yoshikazu Yonemitsu ,  Makoto Inoue ,  Yumiko Tokusumi ,  Mamoru Hasegawa

IPC分类号： A61K31/7105 ,  C12N15/74 ,  A61P25/28

CPC分类号： C12N15/86 ,  A61K2039/5256 ,  A61K2039/543 ,  A61K2039/57 ,  C07K14/4711 ,  C12N2760/18843 ,  C12N2800/30

摘要： An objective of the present invention is to provide a safe and effective vaccine therapy for Alzheimer's disease. A minus strand RNA viral vector carrying amyloid gene was constructed, and administered intranasally to 24- to 25-months-old APP transgenic mice. The level of serum anti-A 42 antibody was determined and showed to be markedly higher than the control. The results of histological investigation showed that the administration of a vector of the present invention markedly reduced senile plaques in all of the frontal lobe, parietal lobe, and hippocampus. The brain A level was also markedly reduced. Furthermore, the administration of a vector of the present invention did not result in lymphocyte infiltration in the central nervous system.

摘要翻译： 本发明的目的是为阿尔茨海默病提供安全有效的疫苗疗法。 构建携带淀粉样蛋白基因的负链RNA病毒载体，鼻内给予24至25个月大的APP转基因小鼠。 测定血清抗-A42抗体水平，显示明显高于对照组。 组织学研究结果表明，施用本发明的载体显着降低了所有额叶，顶叶和海马中的老年斑。 脑A水平也明显降低。 此外，本发明的载体的施用不会导致中枢神经系统中的淋巴细胞浸润。

公开(公告)号：US20050130123A1

公开(公告)日：2005-06-16

申请号：US10489384

申请日：2002-09-18

申请人： Makoto Inoue ,  Yumiko Tokusumi ,  Akihiro Iida ,  Mamoru Hasegawa

发明人： Makoto Inoue ,  Yumiko Tokusumi ,  Akihiro Iida ,  Mamoru Hasegawa

IPC分类号： A61K48/00 ,  C12N7/01 ,  C12N7/04 ,  C12N15/45 ,  C12N15/86 ,  C12Q1/70 ,  C12N15/867 ,  C12Q1/68

CPC分类号： C12N7/00 ,  A61K48/00 ,  C12N15/86 ,  C12N2760/18843 ,  C12N2760/18861 ,  C12N2800/30

摘要： The present invention provides methods for testing and producing (−) strand RNA virus vectors with reduced or eliminated particle formation ability or cytotoxicity. It was revealed that a deficiency in M protein localization in cells introduced with such a (−) strand RNA virus vector could result in the suppression of virus-like particle (VLP) formation in the cells. The present invention provides methods for testing and screening for a (−) strand RNA virus vector in which particle formation ability has been reduced or eliminated, and methods for producing a recombinant (−) strand RNA virus vector in which particle formation ability has been reduced or eliminated. Such a vector, in which VLP formation has been reduced or eliminated, is extremely useful as a vector for gene therapy, since it neither induces cytotoxicity nor immune response due to the secondary release of viruses from cells in which it has been introduced.

摘要翻译： 本发明提供了测试和生产（ - ）链RNA病毒载体的方法，其具有降低或消除的颗粒形成能力或细胞毒性。 显示出用这种（ - ）链RNA病毒载体引入的细胞中M蛋白定位的缺陷可导致细胞中病毒样颗粒（VLP）形成的抑制。 本发明提供了用于测定和筛选其中减少或消除了颗粒形成能力的（ - ）链RNA病毒载体的方法，以及用于生产其中颗粒形成能力已经降低的重组（ - ）链RNA病毒载体的方法 或消除。 已经减少或消除VLP形成的这种载体作为用于基因治疗的载体是非常有用的，因为它既不引起细胞毒性也不诱导免疫应答，这是由于病毒从其引入细胞的二次释放引起的。

公开(公告)号：US20090246170A1

公开(公告)日：2009-10-01

申请号：US12302927

申请日：2007-05-31

申请人： Makoto Inoue ,  Yumiko Tokusumi ,  Hitoshi Iwasaki ,  Hiroto Hara ,  Toshiaki Tabata ,  Mamoru Hasegawa

发明人： Makoto Inoue ,  Yumiko Tokusumi ,  Hitoshi Iwasaki ,  Hiroto Hara ,  Toshiaki Tabata ,  Mamoru Hasegawa

IPC分类号： A61K38/20 ,  A61K31/7088 ,  A61K38/19 ,  A61K38/02 ,  A61P25/28

CPC分类号： A61K35/76 ,  A61K38/2026 ,  A61K38/2066 ,  A61K38/2086 ,  A61K48/00 ,  C07K14/5428 ,  C12N15/86 ,  C12N2760/18843 ,  A61K2300/00

摘要： The present invention provides novel therapeutic methods and agents for treating Alzheimer's disease. Specifically, the present invention relates to anti-inflammatory cytokines, anti-inflammatory cytokine genes, negative-strand RNA viral vectors carrying an anti-inflammatory cytokine gene, which are used for treating Alzheimer's disease or developing therapeutic agents for Alzheimer's disease. The present invention also provides pharmaceutical compositions for treating or preventing Alzheimer's disease, which comprise the cytokines or vectors. The present invention further provides methods for treating Alzheimer's disease, which comprise the step of administering an anti-inflammatory cytokine, or a vector such as a negative-strand RNA viral vector carrying an anti-inflammatory cytokine gene. The present invention enables novel gene therapies for Alzheimer's disease.

摘要翻译： 本发明提供治疗阿尔茨海默氏病的新型治疗方法和药剂。 具体而言，本发明涉及抗炎细胞因子，抗炎细胞因子基因，携带抗炎细胞因子基因的负链RNA病毒载体，其用于治疗阿尔茨海默病或开发阿尔茨海默氏病的治疗剂。 本发明还提供了用于治疗或预防阿尔茨海默病的药物组合物，其包含细胞因子或载体。 本发明还提供了治疗阿尔茨海默病的方法，其包括施用抗炎细胞因子的步骤，或携带抗炎细胞因子基因的载体如负链RNA病毒载体。 本发明使得能够进行阿尔茨海默病的新基因治疗。

公开(公告)号：US07226786B2

公开(公告)日：2007-06-05

申请号：US10316535

申请日：2002-12-10

申请人： Kaio Kitazato ,  Tsugumine Shu ,  Hidekazu Kuma ,  Yasuji Ueda ,  Makoto Asakawa ,  Mamoru Hasegawa ,  Akihiro Iida ,  Fumino Tokito ,  Takahiro Hirata ,  Tsuyoshi Tokusumi ,  Makoto Inoue ,  Yumiko Tokusumi

发明人： Kaio Kitazato ,  Tsugumine Shu ,  Hidekazu Kuma ,  Yasuji Ueda ,  Makoto Asakawa ,  Mamoru Hasegawa ,  Akihiro Iida ,  Fumino Tokito ,  Takahiro Hirata ,  Tsuyoshi Tokusumi ,  Makoto Inoue ,  Yumiko Tokusumi

IPC分类号： C12N15/00 ,  C12N15/86

CPC分类号： C12N15/86 ,  A61K48/00 ,  A61K2039/5254 ,  A61K2039/5256 ,  C12N7/00 ,  C12N2760/18823 ,  C12N2760/18843 ,  C12N2760/18845 ,  C12N2760/18861 ,  C12N2800/30 ,  C12N2810/6081

摘要： F gene-deficient virus virions are successfully recovered by using an F gene-deficient Sendai virus genomic cDNA. Further, F gene-deficient infectious viral particles are successfully constructed by using F-expressing cells as helper cells. Also, F gene and HN gene-deficient virus virions are successfully recovered by using a virus genomic cDNA deficient in both F gene and HN gene. Further, F gene and HN gene-deficient infectious viral particles are successfully produced by using F- and HN-expressing cells as helper cells. A virus deficient in F gene and HN gene and having F protein is constructed by using F-expressing cells as helper cells. In addition, M gene-deficient infectious virus particles were produced using helper cells expressing M protein. From cells infected with M gene-deficient viruses, release of virus-like particles was inhibited. Further, a VSV-G pseudo type virus is successfully constructed by using VSV-G-expressing cells. Techniques for constructing these deficient viruses contribute to the development of vectors of Paramyxoviridae usable in gene therapy.

摘要翻译： 通过使用F基因缺陷的仙台病毒基因组cDNA成功地回收了F基因缺陷型病毒粒子。 此外，通过使用F表达细胞作为辅助细胞，成功构建了F基因缺陷型感染性病毒颗粒。 此外，通过使用F基因和HN基因缺陷的病毒基因组cDNA，成功地回收了F基因和HN基因缺陷型病毒粒子。 此外，通过使用F-和HN表达细胞作为辅助细胞，F基因和HN基因缺陷型感染性病毒颗粒成功产生。 通过使用F表达细胞作为辅助细胞构建F基因和HN基因并具有F蛋白的病毒。 此外，使用表达M蛋白的辅助细胞产生M基因缺陷型感染性病毒颗粒。 从感染M基因缺陷病毒的细胞中，病毒样颗粒的释放被抑制。 此外，通过使用表达VSV-G的细胞成功地构建了VSV-G伪型病毒。 用于构建这些缺陷病毒的技术有助于可用于基因治疗的副粘病毒科的载体的发育。

公开(公告)号：US20070009949A1

公开(公告)日：2007-01-11

申请号：US11515341

申请日：2006-09-01

申请人： Kaio Kitazato ,  Tsugumine Shu ,  Hidekazu Kuma ,  Yasuji Ueda ,  Makoto Asakawa ,  Mamoru Hasegawa ,  Akihiro Iida ,  Takahiro Hirata ,  Makoto Inoue ,  Yumiko Tokusumi

发明人： Kaio Kitazato ,  Tsugumine Shu ,  Hidekazu Kuma ,  Yasuji Ueda ,  Makoto Asakawa ,  Mamoru Hasegawa ,  Akihiro Iida ,  Takahiro Hirata ,  Makoto Inoue ,  Yumiko Tokusumi

IPC分类号： C12Q1/68 ,  C12N7/00 ,  C12N5/00 ,  C12N7/01 ,  C12N5/02

CPC分类号： C07K14/005 ,  A61K48/00 ,  A61K2039/5254 ,  A61K2039/5256 ,  C12N7/00 ,  C12N15/86 ,  C12N2710/24143 ,  C12N2760/18811 ,  C12N2760/18822 ,  C12N2760/18823 ,  C12N2760/18843 ,  C12N2760/18845 ,  C12N2760/18861 ,  C12N2760/20222 ,  C12N2800/30 ,  C12N2810/6081

摘要： A functional RNP containing negative-strand single-stranded RNA derived from Sendai virus, which has been modified so as not to express at least one envelope protein, has been successfully prepared. An RNP comprising a foreign gene is prepared and inserted into a cell with the use of a cationic liposome, thereby successfully expressing the foreign gene.

摘要翻译： 已经成功地制备了已经被修饰以便不表达至少一种包膜蛋白的来源于仙台病毒的负链单链RNA的功能性RNP。 制备包含外来基因的RNP，并使用阳离子脂质体将其插入细胞中，从而成功地表达外源基因。

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。

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。

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。

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。

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。