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1. 发明申请

US20160060314A1 Development of a Protein-Based Biotherapeutic Agent That Penetrates Cell-Membrane and Induces Anti-Tumor Effect in Solid Tumors - Improved Cell-Permeable Suppressor of Cytokine Signaling (iCP-SOCS3) Proteins, Polynucleotides Encoding the Same, and Anti-Tumor Compositions Comprising the Same 审中-公开
公开(公告)号：US20160060314A1
公开(公告)日：2016-03-03
申请号：US14838304
申请日：2015-08-27
申请人： DAEWOONG JO , Cellivery Therapeutics, Inc.
发明人： Daewoong JO , Young Sil CHOI , Seul Mee SHIN , Ju Hyun NAM
IPC分类号： C07K14/47 , C07K7/08
摘要： In principle, protein-based biotherapeutics offers a way to control biochemical processes in living cells under non-steady state conditions and with fewer off-target effects than conventional small molecule therapeutics. However, systemic protein delivery in vivo has been proven difficult due to poor tissue penetration and rapid clearance. Protein transduction exploits the ability of some cell-penetrating peptide (CPP) sequences to enhance the uptake of proteins and other macromolecules by mammalian cells. Previously developed hydrophobic CPPs, named membrane translocating sequence (MTS), membrane translocating motif (MTM) and macromolecule transduction domain (MTD), are able to deliver biologically active proteins into a variety of cells and tissues. Various cargo proteins fused to these CPPs have been used to test the functional and/or therapeutic efficacy of protein transduction. The recombinant proteins consisting of suppressor of cytokine signaling 3 (CP-SOCS3) protein fused to the fibroblast growth factor (FGF) 4-derived MTM were developed to inhibit inflammation and apoptosis. However, CP-SOCS3 fusion proteins expressed in bacteria cells were hard to be purified in soluble form. To address these critical limitations, CPP sequences called advanced MTDs (aMTDs) have been developed in this art. This is accomplished by (i) analyzing previous developed hydrophobic CPP sequences to identify specific critical factors (CFs) that affect intracellular delivery potential and (ii) constructing artificial aMTD sequences satisfied for each critical factor. In addition, solubilization domains (SDs) have been incorporated into the aMTD-fused SOCS3 recombinant proteins to enhance solubility with corresponding increases in protein yield and cell-/tissue-permeability. These recombinant SOCS3 proteins fused to aMTD/SD having much higher solubility/yield and cell-/tissue-permeability have been named as improved cell-permeable SOCS3 (iCP-SOCS3) proteins. Previously developed CP-SOCS3 proteins fused to MTM were only tested or used as anti-inflammatory agents to treat acute liver injury. In the present art, iCP-SOCS3 proteins have been tested for use as anti-cancer agents in the treatment of various cancers likes gastric, colorectal and breast cancer, and glioblastoma. Since SOCS3 is frequently deleted in and loss of SOCS3 in tumors promotes resistance to apoptosis and proliferation, we reasoned that iCP-SOCS3 could be used as a protein-based intracellular replacement therapy for the treatment of various cancers. The results demonstrated in this art support the reasoning: treatment of cancer cells with iCP-SOCS3 results in reduced cancer cell viability, enhanced apoptosis of solid tumors including gastric, colorectal and breast cancer, and glioblastoma and loss of cell migration/invasion potential. Furthermore, iCP-SOCS3 inhibits the growth of gastric and colorectal tumors in a subcutaneous xenografts model. In the present invention with iCP-SOCS3, where SOCS3 is fused to an empirically determined combination of newly developed aMTD and customized SD, macromolecule intracellular transduction technology (MITT) enabled by the advanced MTDs may provide novel protein therapy against various tumors such as gastric cancer, colorectal cancer, glioblastoma, and breast cancer.

2. 发明申请

US20160060310A1 Development of Protein-Based Biotherapeutics That Penetrates Cell-Membrane and Induces Anti-Hepatocellular Carcinoma Effect - Improved Cell-Permeable Suppressor of Cytokine Signaling (iCP-SOCS3) Proteins, Polynucleotides Encoding the Same, and Anti-Hepatocellular Carcinoma Compositions Comprising the Same 审中-公开
公开(公告)号：US20160060310A1
公开(公告)日：2016-03-03
申请号：US14838260
申请日：2015-08-27
申请人： DAEWOONG JO , Cellivery Therapeutics, Inc.
发明人： Daewoong JO , Young Sil CHOI , Youn Seo HWANG , Kyeong Soo KIM
IPC分类号： C07K14/47 , C07K7/08
摘要： Protein transduction exploits the ability of some cell-penetrating peptide (CPP) sequences to enhance the uptake of proteins and other macromolecules by mammalian cells. Previously developed hydrophobic CPPs, named membrane translocating sequence (MTS), membrane translocating motif (MTM) and macromolecule transduction domain (MTD), are able to deliver biologically active proteins into a variety of cells and tissues. Various cargo proteins fused to these CPPs have been used to test the functional and/or therapeutic efficacy of protein transduction. For example, recombinant proteins consisting of suppressor of cytokine signaling 3 protein (CP-SOCS3) fused to the fibroblast growth factor (FGF) 4-derived MTM were developed to inhibit inflammation and apoptosis. However, CP-SOCS3 fusion proteins expressed in bacteria were hard to purify in soluble form. To address these critical limitations, CPP sequences called advanced MTDs (aMTD) have been developed in this art. This is accomplished by (i) analyzing previous developed hydrophobic CPP sequences to identify specific critical factors (CFs) that affect intracellular delivery potential and (ii) constructing artificial aMTD sequences satisfied for each critical factor. In addition, solubilization domains (SDs) have been incorporated into the aMTD-fused SOCS3 recombinant proteins to enhance solubility with corresponding increases in protein yield and cell-/tissue-permeability. These recombinant SOCS3 proteins fused to aMTD/SD having much higher solubility/yield and cell-/tissue-permeability have been named as improved cell-permeable SOCS3 (iCP-SOCS3) proteins. Previously developed CP-SOCS3 proteins fused to MTM were only tested or used as anti-inflammatory agents to treat acute liver injury. In the present art, iCP-SOCS3 proteins have been tested for use as anti-cancer agents in the treatment of hepatocellular carcinoma. Since SOCS3 is frequently deleted in and loss of SOCS3 in hepatocytes promotes resistance to apoptosis and proliferation, we reasoned that iCP-SOCS3 could be used as a protein-based intracellular replacement therapy for the treatment of hepatocellular carcinoma. The results support this reasoning: treatment of hepatocellular carcinoma cells with iCP-SOCS3 results in reduced cancer cell viability, enhanced apoptosis and loss of cell migration/invasion potential. Furthermore, iCP-SOCS3 inhibits the growth of hepatocellular carcinoma in a subcutaneous xenografts model. In the present invention with iCP-SOCS3 fused to an empirically determined combination of newly developed aMTD and customized SD, macromolecule intracellular transduction technology (MITT) enabled by the advanced MTD may provide novel protein therapy against hepatocellular carcinoma.

3. 发明申请

US20160060312A1 Development of Protein-Based Biotherapeutics That Penetrates Cell-Membrane and Induces Anti-Pancreatic Cancer Effect - Improved Cell-Permeable Suppressor of Cytokine Signaling (iCP-SOCS3) Proteins, Polynucleotides Encoding the Same, and Anti-Pancreatic Cancer Compositions Comprising the Same 审中-公开
公开(公告)号：US20160060312A1
公开(公告)日：2016-03-03
申请号：US14838288
申请日：2015-08-27
申请人： Daewoong JO , Cellivery Therapeutics, Inc.
发明人： Daewoong JO , Young Sil CHOI , Eun Kyung LEE , Na Ra YOON
IPC分类号： C07K14/47 , C07K7/08
摘要： In principle, protein-based biotherapeutics offers a way to control biochemical processes in living cells under non-steady state conditions and with fewer off-target effects than conventional small molecule therapeutics. However, systemic protein delivery in vivo has been proven difficult due to poor tissue penetration and rapid clearance. Protein transduction exploits the ability of some cell-penetrating peptide (CPP) sequences to enhance the uptake of proteins and other macromolecules by mammalian cells. Previously developed hydrophobic CPPs, named membrane translocating sequence (MTS), membrane translocating motif (MTM) and macromolecule transduction domain (MTD), are able to deliver biologically active proteins into a variety of cells and tissues. Various cargo proteins fused to these CPPs have been used to test the functional and/or therapeutic efficacy of protein transduction. The recombinant proteins consisting of suppressor of cytokine signaling 3 (CP-SOCS3) protein fused to the fibroblast growth factor (FGF) 4-derived MTM were developed to inhibit inflammation and apoptosis. However, CP-SOCS3 fusion proteins expressed in bacteria cells were hard to be purified in soluble form. To address these critical limitations, CPP sequences called advanced MTDs (aMTDs) have been developed in this art. This is accomplished by (i) analyzing previous developed hydrophobic CPP sequences to identify specific critical factors (CFs) that affect intracellular delivery potential and (ii) constructing artificial aMTD sequences that satisfy each critical factor. In addition, solubilization domains (SDs) have been incorporated into the aMTD-fused SOCS3 recombinant proteins to enhance solubility with corresponding increases in protein yield and cell-/tissue-permeability. These recombinant SOCS3 proteins fused to aMTD/SD having much higher solubility/yield and cell-/tissue-permeability have been named as improved cell-permeable SOCS3 (iCP-SOCS3) proteins. Previously developed CP-SOCS3 proteins fused to MTM were only tested or used as anti-inflammatory agents to treat acute liver injury. In the present art, iCP-SOCS3 proteins have been tested for use as anti-cancer agents in the treatment of pancreatic cancer. Since SOCS3 is frequently deleted in cancer cells and loss of SOCS3 promotes resistance to apoptosis and proliferation, we reasoned that iCP-SOCS3 could be used as a protein-based intracellular replacement therapy for the treatment of pancreatic cancer. The results demonstrated in this art support this reasoning: treatment of pancreatic cancer cells with iCP-SOCS3 results in reduced cancer cell viability, enhanced apoptosis and loss of cell migration/invasion potentials. Furthermore, iCP-SOCS3 inhibits the growth of pancreatic cancer in a subcutaneous xenografts model. In the present invention with iCP-SOCS3, where SOCS3 is fused to an empirically determined combination of newly developed aMTD and customized SD, macromolecule intracellular transduction technology (MITT) enabled by the advanced MTDs may provide novel protein therapy against pancreatic cancer.

4. 发明申请

US20160060311A1 Development of Protein-Based Biotherapeutics That Penetrates Cell-Membrane and Induces Anti-Lung Cancer Effect - Improved Cell-Permeable Suppressor of Cytokine Signaling (iCP-SOCS3) Proteins, Polynucleotides Encoding the Same, and Anti-Lung Cancer Compositions Comprising the Same 审中-公开
公开(公告)号：US20160060311A1
公开(公告)日：2016-03-03
申请号：US14838280
申请日：2015-08-27
申请人： Daewoong JO , Cellivery Therapeutics, Inc.
发明人： Daewoong JO , Young Sil CHOI , Kuy Sook LEE , Min Seok JANG
IPC分类号： C07K14/47 , C07K7/08
摘要： In principle, protein-based biotherapeutics offers a way to control biochemical processes in living cells under non-steady state conditions and with fewer off-target effects than conventional small molecule therapeutics. However, systemic protein delivery in vivo has been proven difficult due to poor tissue penetration and rapid clearance. Protein transduction exploits the ability of some cell-penetrating peptide (CPP) sequences to enhance the uptake of proteins and other macromolecules by mammalian cells. Previously developed hydrophobic CPPs, named membrane translocating sequence (MTS), membrane translocating motif (MTM) and macromolecule transduction domain (MTD), are able to deliver biologically active proteins into a variety of cells and tissues. Various cargo proteins fused to these CPPs have been used to test the functional and/or therapeutic efficacy of protein transduction. Previously, recombinant proteins consisting of suppressor of cytokine signaling 3 (CP-SOCS3) protein fused to the fibroblast growth factor (FGF) 4-derived MTM were developed to inhibit inflammation and apoptosis. However, CP-SOCS3 fusion proteins expressed in bacteria cells were hard to be purified in soluble form. To address these critical limitations, CPP sequences called advanced MTDs (aMTDs) have been developed in this art. The development of this art has been accomplished by (i) analyzing previous developed hydrophobic CPP sequences to identify specific critical factors (CFs) that affect intracellular delivery potential and (ii) constructing artificial aMTD sequences that satisfy for each critical factor. In addition, solubilization domains (SDs) have been incorporated into the aMTD-fused SOCS3 recombinant proteins to enhance solubility with corresponding increases in protein yield and cell-/tissue-permeability. These recombinant SOCS3 proteins fused to aMTD/SD having much higher solubility/yield and cell-/tissue-permeability have been named as improved cell-permeable SOCS3 (iCP-SOCS3) proteins. Previously developed CP-SOCS3 proteins fused to MTM were only tested or used as anti-inflammatory agents to treat acute liver injury. In the present art, iCP-SOCS3 proteins have been tested for use as anti-cancer agents in the treatment of neoplasia in lung. Since SOCS3 is frequently deleted in cancer cells and loss of SOCS3 promotes resistance to apoptosis and proliferation, we reasoned that iCP-SOCS3 could be used as a protein-based intracellular replacement therapy for the treatment of lung cancer. The results demonstrated in this art support this reasoning: treatment of human non-small cell lung carcinoma cells with iCP-SOCS3 results in reduced cancer cell viability, enhanced apoptosis. Furthermore, iCP-SOCS3 inhibited migration/invasion of lung cancer cells. In the present invention with iCP-SOCS3, where SOCS3 is fused to an empirically determined combination of newly developed aMTD and customized SD, macromolecule intracellular transduction technology (MITT) enabled by the advanced MTDs may provide novel protein therapy against lung cancer.

5. 发明授权

US08470971B2 Cell permeable p53 recombinant protein, polynucleotide encoding the same, and anti-cancer composition containing the same as active ingredient 有权
标题翻译：细胞可渗透的p53重组蛋白，编码它们的多核苷酸以及含有与活性成分相同的抗癌组合物
公开(公告)号：US08470971B2
公开(公告)日：2013-06-25
申请号：US13132202
申请日：2009-12-02
申请人： Daewoong Jo , Jung-Hee Lim
发明人： Daewoong Jo , Jung-Hee Lim
IPC分类号： C07K7/00
CPC分类号： C07K14/4746 , A61K38/00 , C07K2319/10
摘要： Disclosed are a cell-permeable p53 recombinant protein in which a macromolecule transduction domain (MTD) is fused to the tumor suppressor p53, a polynucleotide encoding the same, a recombinant expression vector for producing the same, and a pharmaceutical composition of the treatment of cancer, comprising the same. Having high cell permeability, the p53 recombinant protein is effectively transduced into cells so that the tumor suppressor p53 can be translocated into cell nuclei. Within nuclei, p53 inhibits the formation of cyclin-CDK complexes to halt the cell cycle, thus suppressing excessive cell proliferation and inducing apoptosis of tumor cells. Therefore, the p53 recombinant protein can be useful as an anticancer agent in the treatment of various cancers.
摘要翻译：公开了一种细胞可渗透的p53重组蛋白，其中大分子转导结构域（MTD）与肿瘤抑制基因p53融合，编码该多核苷酸的多核苷酸，用于制备该多核苷酸的重组表达载体，以及治疗癌症的药物组合物，包括它们。具有高细胞通透性，p53重组蛋白有效转导入细胞，使肿瘤抑制基因p53能够转位入细胞核。在核内，p53抑制细胞周期蛋白CDK复合物的形成，以阻止细胞周期，从而抑制过量的细胞增殖并诱导肿瘤细胞凋亡。因此，p53重组蛋白可用作治疗各种癌症的抗癌剂。

6. 发明申请

US20110092441A1 CELL-PERMEABLE ENDOSTATIN RECOMBINANT PROTEIN, A POLYNUCLEOTIDE ENCODING THE SAME, AND AN ANTI-CANCER PREPARATION CONTAINING THE SAME AS AN ACTIVE COMPONENT 有权
标题翻译：细胞内皮素内质网蛋白重组蛋白，编码其的多核苷酸和包含其中的活性成分的抗癌制剂
公开(公告)号：US20110092441A1
公开(公告)日：2011-04-21
申请号：US12936334
申请日：2009-04-03
申请人： Daewoong Jo , Jong Min Lee , Kyoungho Park , Minh Tam Duong
发明人： Daewoong Jo , Jong Min Lee , Kyoungho Park , Minh Tam Duong
IPC分类号： A61K38/02 , C07K2/00 , C07K14/47 , C07H21/00 , C07H21/04 , C12N15/63 , C12N1/21 , C12P21/02 , A61P35/00
CPC分类号： C07K14/78 , A61K38/17 , C07K2319/01
摘要： The present invention relates to a cell-permeable endostatin recombinant protein in which a macromolecule transduction domain (MTD) is fused to an angiogenesis inhibitor (angiogenesis inhibitor) endostatin; a polynucleotide encoding the cell-permeable endostatin recombinant protein; an expression vector for the cell-permeable endostatin recombinant protein; and a pharmacological composition for an anti-cancer preparation with improved inhibitory activity against angiogenesis in cancer, which contains the cell-permeable endostatin recombinant protein as an active component. The cell-permeable endostatin recombinant protein according to the present invention can block the formation of microvessels and inhibit the migration, proliferation, penetration, tube formation and the like of vascular endothelial cells present in tumor tissue by introducing the angiogenesis inhibitor endostatin into the cell with high efficiency, and it exhibits outstanding anti-cancer activity and so can be used as an anti-cancer drug against various cancers.
摘要翻译：本发明涉及一种细胞可渗透的内皮抑素重组蛋白，其中大分子转导结构域（MTD）与血管生成抑制剂（血管发生抑制剂）内皮抑制素融合; 编码细胞可渗透内皮抑素重组蛋白的多核苷酸; 用于细胞可渗透内皮抑素重组蛋白的表达载体; 以及含有对细胞可渗透内皮抑素重组蛋白作为活性成分的癌症中血管生成抑制活性改善的抗癌剂的药理学组合物。根据本发明的细胞可渗透的内皮抑素重组蛋白可以通过将血管生成抑制剂内皮抑制素引入细胞中来阻断微血管的形成并抑制存在于肿瘤组织中的血管内皮细胞的迁移，增殖，穿透，管形成等效率高，具有突出的抗癌活性，可作为抗癌药物用于各种癌症。

7. 发明申请

US20110021442A1 CELL PREAMBLE RUNX3 RECOMBINANT PROTEINS, POLYNUCLEOTIDES ENCODING THE SAME, AND ANTICANCER COMPOSITIONS INCLUDING THE SAME 审中-公开
标题翻译：细胞前体RUNX3重组蛋白，编码其的多核苷酸和包括其的抗体组合物
公开(公告)号：US20110021442A1
公开(公告)日：2011-01-27
申请号：US12741138
申请日：2008-11-06
申请人： Daewoong Jo , Eun Kyung Hong , Jung-Hee Lim , Se-Eun Kang , Lihua Che
发明人： Daewoong Jo , Eun Kyung Hong , Jung-Hee Lim , Se-Eun Kang , Lihua Che
IPC分类号： A61K38/00 , C07K14/00 , C07H21/04 , C12N15/63 , C12N1/21 , C12P21/06 , A61P35/00 , A61P35/04
CPC分类号： C07K14/4702 , C07K2319/09 , C07K2319/10 , C07K2319/21
摘要： The present invention discloses cell permeable RUNX3 recombinant proteins where a Macromolecule Transduction Domain (MTD) is fused to a tumor and metastasis suppressor RUNX3. Also disclosed are polynucleotides encoding the cell permeable RUNX3 recombinant proteins, an expression vector containing the cell permeable RUNX3 recombinant protein, and a pharmaceutical composition for preventing metastasis which contains the cell permeable RUNX3 recombinant protein as an effective ingredient. The cell permeable RUNX3 recombinant proteins of the present invention can induce the reactivation of TGF-β signal transduction pathway which causes cell cycle arrest by efficiently introducing a tumor and metastasis suppressor RUNX3 into a cell. Therefore, the cell permeable RUNX3 recombinant proteins of the present invention can be effectively used as an anticancer agent capable of preventing cancer growth and metastasis by suppressing the proliferation, differentiation, and migration of cancer cells.
摘要翻译：本发明公开了细胞渗透性RUNX3重组蛋白，其中大分子转导结构域（MTD）与肿瘤融合，转移抑制因子RUNX3。还公开了编码细胞可渗透性RUNX3重组蛋白的多核苷酸，含有细胞可渗透性RUNX3重组蛋白的表达载体和用于预防转移的药物组合物，其含有可透过细胞的RUNX3重组蛋白作为有效成分。本发明的细胞渗透性RUNX3重组蛋白可以诱导TGF- 信号转导途径，通过有效地将肿瘤和转移抑制剂RUNX3引入细胞而引起细胞周期阻滞。因此，通过抑制癌细胞的增殖，分化和迁移，本发明的细胞可渗透的RUNX3重组蛋白可以有效地用作能够预防癌症生长和转移的抗癌剂。

8. 发明申请

US20100323971A1 CELL PERMEABLE NM23 RECOMBINANT PROTEINS, POLYNUCLEOTIDES ENCODING THE SAME, AND ANTI-METASTATIC COMPOSITION COMPRISING THE SAME 有权
标题翻译：细胞渗透性NM23重组蛋白，编码其的多核苷酸和包含其的抗细胞组成
公开(公告)号：US20100323971A1
公开(公告)日：2010-12-23
申请号：US12676182
申请日：2008-09-04
申请人： Daewoong Jo , Thi Thuy Nga Do , Kisuk Park
发明人： Daewoong Jo , Thi Thuy Nga Do , Kisuk Park
IPC分类号： A61K38/16 , C12P21/04 , C12N1/21 , C12N15/63 , C07K14/435 , C07H21/04 , A61P35/04
CPC分类号： C12N9/12 , A61K38/1709 , C07K2319/00 , C07K2319/09 , C07K2319/10
摘要： The present invention discloses cell permeable Nm23 recombinant proteins where a macromolecule transduction domain (MTD) is fused to a metastasis suppressor Nm23. Also disclosed are polynucleotides encoding the cell permeable Nm23 recombinant proteins, an expression vector containing the cell permeable Nm23 recombinant protein, and a pharmaceutical composition for preventing metastasis which contains the cell permeable Nm23 recombinant protein as an effective ingredient. The cell permeable Nm23 recombinant proteins of the present invention can induce KSR phosphorylation and inactivation and inhibit Ras-mediated MAPK cascade by efficiently introducing a metastasis suppressor Nm23 into a cell. Therefore, the cell permeable Nm23 recombinant proteins of the present invention can be effectively used as an anti-metastatic agent capable of preventing cancer metastasis by inhibiting the proliferation, differentiation and migration of cancer cells.
摘要翻译：本发明公开了一种细胞渗透性的Nm23重组蛋白，其中大分子转导结构域（MTD）与转移抑制基因Nm23融合。还公开了编码细胞可渗透性的Nm23重组蛋白质的多核苷酸，含有细胞可渗透性的Nm23重组蛋白质的表达载体，以及含有细胞可渗透性的Nm23重组蛋白质作为有效成分的用于预防转移的药物组合物。本发明的细胞可渗透的Nm23重组蛋白可以通过有效地将转移抑制基因Nm23引入细胞来诱导KSR磷酸化和失活并抑制Ras介导的MAPK级联。因此，通过抑制癌细胞的增殖，分化和迁移，本发明的细胞可渗透的Nm23重组蛋白可以有效地用作能够预防癌转移的抗转移剂。

9. 发明申请

US20170137482A1 CELL-PERMEABLE (ICP)-SOCS3 RECOMBINANT PROTEIN AND USES THEREOF 审中-公开
公开(公告)号：US20170137482A1
公开(公告)日：2017-05-18
申请号：US15361701
申请日：2016-11-28
申请人： Daewoong JO , CELLIVERY THERAPEUTICS, INC.
发明人： Daewoong JO , Youngsil CHOI , Kuysook LEE , Seulmee SHIN , Jihye KIM , Jeongmin KIM , Chohyun KIM
IPC分类号： C07K14/47 , C07K7/08
摘要： The present invention relates to providing improved cell-permeable (iCP)-SOCS3 recombinant protein and uses thereof. Preferably, the iCP-SOCS3 recombinant protein may be used as protein-based anti-solid tumor agent by utilizing the platform technology for macromolecule intracellular transduction.

10. 发明申请

US20170029798A1 Development of Improved Cell-Permeable (iCP) Parkin Recombinant Protein as a Protein-Based Anti-Neurodegenerative Agent for the Treatment of Parkinson's Disease-Associated Phenotypes by Utilizing BBB-Penetrating Protein Delivery System MITT, Enabled by Advanced Macromolecule Transduction Domain (aMTD) 审中-公开
标题翻译：通过使用BBB穿透蛋白递送系统MITT，通过高级大分子转导结构域（aMTD）启动，改进的细胞透过性（iCP）Parkin重组蛋白作为基于蛋白质的抗神经变性剂用于治疗帕金森病相关表型的发展
公开(公告)号：US20170029798A1
公开(公告)日：2017-02-02
申请号：US14809279
申请日：2015-07-27
申请人： DAEWOONG JO , Cellivery Therapeutics, Inc.
发明人： Daewoong JO , EUNSIN HA , JIEUN LEE , JEONGMIN JEON , KWANGJAE LEE
IPC分类号： C12N9/00 , G01N33/573
CPC分类号： C12N9/93 , C07K2319/10 , C12Y603/02019 , G01N33/573 , G01N2333/9015
摘要： Macromolecule intracellular transduction technology based on improved cell-permeable Parkin recombinant protein (iCP-Parkin) has been developed as a protein-based anti-neurodegenerative agent for efficient BBB-penetration to effectively deliver the recombinant protein into the brain. Parkin protein, a dopaminergic neuronal cell death inhibitor, has been fused with a newly developed advanced macromolecule transduction domain (aMTD) and solubilization domain (SD) to increase the solubility/yield and cell-/tissue-permeability of the recombinant protein. In addition, our newly developed aMTD/SD-fused recombinant iCP-Parkin protein has shown BBB-permeability. Both in vitro and in vivo, our iCP-Parkin recombinant protein improved motor skills, a typical phenotype of Parkinson's disease, by increasing dopamine level in the brain by suppressing apoptosis of dopaminergic neuron cells. In conclusion, iCP-Parkin could be applicable in clinical studies as a protein-based anti-neurodegenerative agent to treat Parkinson's disease by protecting dopaminergic neuron cells and regulating the secretion of dopamine.
摘要翻译：已经开发了基于改进的细胞可渗透的Parkin重组蛋白（iCP-Parkin）的大分子细胞内转导技术作为用于有效BBB穿透的蛋白质的抗神经变性剂，以有效地将重组蛋白质递送到脑中。 Parkin蛋白是一种多巴胺能神经元细胞死亡抑制剂，与新开发的高分子大分子转导结构域（aMTD）和溶解域（SD）融合，以提高重组蛋白的溶解度/产量和细胞/组织通透性。另外，我们新开发的aMTD / SD融合重组iCP-Parkin蛋白显示了BBB通透性。在体外和体内，我们的iCP-Parkin重组蛋白通过抑制多巴胺能神经元细胞的凋亡来增加大脑中多巴胺水平，从而改善运动技能，这是帕金森病的典型表型。总之，iCP-Parkin可以作为一种基于蛋白质的抗神经变性药物进行临床研究，通过保护多巴胺能神经元细胞和调节多巴胺的分泌来治疗帕金森病。

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