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1. 发明申请

WO2006091729A3 REVASCULARIZATION OF ISCHEMIC RETINAL TISSUE AND SCREENING METHOD THEREFOR 审中-公开
标题翻译：异位视网膜组织的重新形成及其筛选方法
公开(公告)号：WO2006091729A3
公开(公告)日：2007-03-01
申请号：PCT/US2006006402
申请日：2006-02-24
申请人： SCRIPPS RESEARCH INST , FRIEDLANDER MARTIN , BANIN EYAL , AGUILAR EDITH
发明人： FRIEDLANDER MARTIN , BANIN EYAL , AGUILAR EDITH
IPC分类号： A01N37/18 , A61K38/00 , G01N33/567
CPC分类号： A61K49/0008 , A61K38/53 , C12Y601/01002 , G01N33/5088 , G01N2333/515 , G01N2800/164
摘要： The present invention provides a treatment method for promoting beneficial physiological revascularization of ischemic retinal tissue. The method comprises administering to a mammal suffering from a retinal vascular ischemia a therapeutically effective amount of an angiostatic fragment of tryptophanyl-tRNA synthetase (TrpRS), thereby simultaneously inhibiting pathological neovascularization while promoting beneficial physiological revascularization of damaged areas of the retina. In a preferred embodiment, the angiostatic fragment of TrpRS is T2-TrpRS or T2-TrpRS-GD. Preferably, the mammal is a human patient suffering from retinal ischemia. A screening method for identifying and evaluating therapeutic agents for treating retinal neovascular diseases is also disclosed.
摘要翻译：本发明提供了促进缺血性视网膜组织的有益生理血运重建的治疗方法。该方法包括向患有视网膜血管缺血的哺乳动物施用治疗有效量的色氨酰-tRNA合成酶（TrpRS）的血管生成抑制片段，从而同时抑制病理性新血管形成，同时促进视网膜损伤区域的有益生理血运重建。在优选的实施方案中，TrpRS的血管抑制性片段是T2-TrpRS或T2-TrpRS-GD。优选地，哺乳动物是患有视网膜缺血的人类患者。还公开了用于鉴定和评价用于治疗视网膜新生血管疾病的治疗剂的筛选方法。

2. 发明申请

WO2006091895A3 METHOD FOR THE TREATMENT OF RETINOPATHY OF PREMATURITY AND RELATED RETINOPATHIC DISEASES 审中-公开
标题翻译：治疗前列腺疾病及相关再发性疾病的方法
公开(公告)号：WO2006091895A3
公开(公告)日：2008-09-12
申请号：PCT/US2006006744
申请日：2006-02-24
申请人： SCRIPPS RESEARCH INST , FRIEDLANDER MARTIN , BANIN EYAL , AGUILAR EDITH
发明人： FRIEDLANDER MARTIN , BANIN EYAL , AGUILAR EDITH
IPC分类号： C12N15/00 , A01N63/00 , A01N65/00 , C12N5/0789
CPC分类号： A61K48/00 , A61K31/137 , A61K2035/124 , C12N5/0647 , C12N2510/00 , C12N2510/02
摘要： The present invention provides a method for treating retinopathy of prematurity (ROP) and related retinopathic diseases. The method comprises administering to the retina of a mammal suffering from, or at risk of developing, retinopathy of prematurity or a related retinopathic disease an amount of cells from a vasculotrophic lineage negative hematopoietic stem cell population, effective to promote beneficial physiological revascularization of damaged areas of the retina and to ameliorate damage to the retina caused by the disease. Preferably, the mammal is a human patient. In one preferred embodiment, the lineage negative hematopoietic stem cell population is a lineage negative hematopoietic stem cell population comprising hematopoietic stem cells and endothelial progenitor cells (i.e., Lin- HSC). In another preferred embodiment, the lineage negative hematopoietic stem cell population is an isolated myeloid-like bone marrow (MLBM) cell population in which the majority of the cells are lineage negative and express CD44 antigen and CD11b antigen. As an alternative, for treatment of newborn infants, a lineage negative hematopoietic stem cell population can be isolated from umbilical cord vein blood.
摘要翻译：本发明提供了治疗早产儿视网膜病变（ROP）和相关视网膜病变的方法。该方法包括向患有或具有发展为早产儿视网膜病变或相关视网膜病变的哺乳动物的视网膜施用来自血管营养谱系的造血干细胞群体的一定数量的细胞，其有效促进损伤区域的有益生理血运重建的视网膜，并改善由该疾病引起的视网膜损伤。优选地，哺乳动物是人类患者。在一个优选的实施方案中，谱系负造血干细胞群是包含造血干细胞和内皮祖细胞（即Lin-HSC）的谱系负造血干细胞群。在另一个优选的实施方案中，谱系负造血干细胞群是分离的骨髓样骨髓（MLBM）细胞群，其中大多数细胞是谱系阴性的并且表达CD44抗原和CD11b抗原。作为替代方案，对于新生儿的治疗，可以从脐带静脉血中分离谱系阴性造血干细胞群。

3. 发明申请

WO2006104609A9 ISOLATED MYELOID-LIKE BONE MARROW CELL POPULATIONS AND METHODS OF TREATMENT THEREWITH 审中-公开
标题翻译：分离的MYELOID-likeBONE MARROW细胞群体及其治疗方法
公开(公告)号：WO2006104609A9
公开(公告)日：2007-02-15
申请号：PCT/US2006006411
申请日：2006-02-24
申请人： SCRIPPS RESEARCH INST , FRIEDLANDER MARTIN , RITTER MATTHEW R , MORENO STACEY K
发明人： FRIEDLANDER MARTIN , RITTER MATTHEW R , MORENO STACEY K
IPC分类号： C12N5/071 , A61K35/00 , C12N5/078
CPC分类号： C12N5/0647 , A61K2035/124 , C12N5/0692
摘要： The present invention provides an isolated myeloid-like bone marrow cell population comprising a majority of cells that are lineage negative, and which express both CD44 antigen and CD11b antigen. These cells have beneficial vasculotrophic and neurotrophic activity when intraocularly administered to the eye of a mammal, particularly a mammal suffering from an ocular degenerative disease. The myeloid-like bone marrow cells are isolated by treating bone marrow cells with an antibody against CD44 (hyaluronic acid receptor), against CD11b, or against both and using flow cytometry to positively select CD44 and/or CD11b expressing cells therefrom. The isolated myeloid-like bone marrow cells of the invention can be transfected with a gene encoding a therapeutically useful protein, for delivering the gene to the retina.
摘要翻译：本发明提供了分离的骨髓样骨髓细胞群，其包含谱系阴性的大多数细胞，并表达CD44抗原和CD11b抗原。当眼内施用于哺乳动物，特别是患有眼变性疾病的哺乳动物的眼睛时，这些细胞具有有益的血管营养和神经营养活性。通过用针对CD11b的抗CD44抗体（透明质酸受体）或针对CD11b的抗体处理骨髓细胞来分离骨髓样细胞，并使用流式细胞术从其中阳性选择表达CD44和/或CD11b的细胞。本发明的分离的骨髓样骨髓细胞可以用编码治疗有用的蛋白质的基因转染，用于将基因递送到视网膜。

4. 发明申请

WO2006031467A3 ISOLATED LINEAGE NEGATIVE HEMATOPOIETIC STEM CELLS AND METHODS OF TREATMENT THEREWITH 审中-公开
标题翻译：分离的线性负性造血干细胞及其治疗方法
公开(公告)号：WO2006031467A3
公开(公告)日：2006-11-02
申请号：PCT/US2005031304
申请日：2005-09-02
申请人： SCRIPPS RESEARCH INST , FRIEDLANDER MARTIN , OTANI ATSUSHI , DA SILVA KAREN , MORENO STACEY HANEKAMP
发明人： FRIEDLANDER MARTIN , OTANI ATSUSHI , DA SILVA KAREN , MORENO STACEY HANEKAMP
IPC分类号： A01N63/00 , C12N15/09 , A01N65/00 , A61K35/12 , A61K35/28 , A61K48/00 , A61P9/10 , A61P27/02 , C12N5/00 , C12N5/02 , C12N5/078 , C12N5/0789 , C12N5/10
CPC分类号： C12N5/0647 , A61K48/00 , A61K2035/124 , C12N5/0692
摘要： Isolated, mammalian, adult bone marrow-derived, lineage negative hematopoietic stem cell population (Lin HSCs) contain endothelial progenitor cells (ECPs) capable of rescuing retinal blood vessels and neuronal networks in the eye. Preferably at least about 20% of the cells in the isolated Lin HSCs express the cell surface antigen CD31. The isolated Lin HSC populations are useful for treatment of ocular vascular diseases and to ameliorate cone cell degeneration in the retina. In a preferred embodiment, the Lin HSCs are isolated by extracting bone marrow from an adult mammal; separating a plurality of monocytes from the bone marrow; labeling the monocytes with biotin-conjugated lineage panel antibodies to one or more lineage surface antigens; removing of monocytes that are positive for the lineage surface antigens from the plurality of monocytes, and recovering a Lin HSCs population containing EPCs. The isolated Lin HSCs also can be transfected with therapeutically useful genes. The treatment may be enhanced by stimulating proliferation of activated astrocytes in the retina using a laser.
摘要翻译：分离的哺乳动物成体骨髓来源的谱系阴性造血干细胞群（Lin HSC）含有能够挽救视网膜血管和眼内神经元网络的内皮祖细胞（ECP）。优选地，分离的Lin HSC中至少约20％的细胞表达细胞表面抗原CD31。分离的Lin HSC群体可用于治疗眼血管疾病并改善视网膜中的视锥细胞变性。在一个优选实施方案中，通过从成年哺乳动物中提取骨髓来分离Lin HSC; 从骨髓分离多个单核细胞; 用针对一种或多种谱系表面抗原的生物素共轭谱系小组抗体标记单核细胞; 从多个单核细胞中去除谱系表面抗原阳性的单核细胞，并回收含EPC的Lin HSC群体。分离的Lin HSC也可以用治疗有用的基因转染。可以通过使用激光刺激视网膜中活化的星形胶质细胞的增殖来增强治疗。

5. 发明申请

WO2006033669A3 METHOD OF MODULATING VASCULARIZATION 审中-公开
标题翻译：调节血管化的方法
公开(公告)号：WO2006033669A3
公开(公告)日：2007-07-05
申请号：PCT/US2005012658
申请日：2005-04-15
申请人： SCRIPPS RESEARCH INST , FRIEDLANDER MARTIN , RUF WOLFRAM , DORRELL MICHAEL , BELTING MATTIAS
发明人： FRIEDLANDER MARTIN , RUF WOLFRAM , DORRELL MICHAEL , BELTING MATTIAS
IPC分类号： A61K38/00 , A61K39/00 , A61K39/395 , A61K48/00 , C07H21/04
CPC分类号： C12N15/86 , A61K38/17 , A61K38/4846 , A61K48/00 , A61K2039/505 , C07K16/36 , C12N2710/10343
摘要： A method of modulating vascularization in a tissue of a mammal comprises controlling a PAR signaling pathway (e.g., the PAR-1 or PAR-2 signaling pathway) in a mammalian tissue, for example, by controlling phosphorylation of tissue factor cytoplasmic domain (i.e., phosphorylation of Ser 258 of the cytoplasmic tail of TF). In a preferred method pathological neovascularization in a mammal is treated by administering to a mammal suffering from pathological neovascularization, a therapeutically effective amount of a PAR signaling pathway inhibitor. Preferably the mammal is a human.
摘要翻译：调节哺乳动物组织中血管形成的方法包括控制哺乳动物组织中PAR信号通路（例如PAR-1或PAR-2信号通路），例如通过控制组织因子细胞质结构域的磷酸化（即， TF的细胞质尾部的Ser255磷酸化）。在优选的方法中，哺乳动物的病理性新生血管形成通过向患有病理性新血管形成的哺乳动物治疗，治疗有效量的PAR信号传导途径抑制剂。优选地，哺乳动物是人。

6. 发明申请

WO2004099232A3 SELECTIVE R-CADHERIN ANTAGONISTS AND METHODS 审中-公开
标题翻译：选择性R-CADHERIN拮抗剂和方法
公开(公告)号：WO2004099232A3
公开(公告)日：2005-05-19
申请号：PCT/US2004013212
申请日：2004-04-30
申请人： SCRIPPS RESEARCH INST , FRIEDLANDER MARTIN , DORRELL MICHAEL I
发明人： FRIEDLANDER MARTIN , DORRELL MICHAEL I
IPC分类号： A61K38/00 , A61K38/06 , A61K38/08 , A61K38/10 , A61K38/12 , C07K20060101 , C07K14/705
CPC分类号： C07K14/705 , A61K38/00
摘要： An isolated peptide useful as a selective antagonist of mammalian R-cadherin comprises 3 to 30 amino acid residues, three contiguous residues of the peptide having the amino acid sequence I1e-Xaa-Ser; wherein Xaa is an amino acid residue selected from the group consisting of Asp, Asn, Glu, and Gln. Preferably Xaa is Asp or Asn. In one preferred embodiment the peptide is a cyclic peptide having 3 to 10 amino acid residues arranged in a ring. The selective R-cadherin antagonist peptides of the invention are useful for inhibiting the targeting of stem cells, such as endothelial precursor cells, to developing vasculature, for inhibiting R-cadherin mediated cellular adhesion, and for inhibiting retinal angiogenesis.
摘要翻译：可用作哺乳动物R-cadherin的选择性拮抗剂的分离的肽包含3-30个氨基酸残基，具有氨基酸序列I1e-Xaa-Ser的肽的三个连续残基; 其中Xaa是选自Asp，Asn，Glu和Gln的氨基酸残基。 Xaa是Asp或Asn。在一个优选实施方案中，肽是以环形排列的具有3至10个氨基酸残基的环肽。本发明的选择性R-钙粘蛋白拮抗剂肽可用于抑制干细胞如内皮前体细胞靶向发展血管，抑制R-cadherin介导的细胞粘附和抑制视网膜血管发生。

7. 发明申请

WO2005117954A3 COMPOSITIONS AND METHODS FOR TREATMENT OF NEOVASCULAR DISEASES 审中-公开
标题翻译：用于治疗新生血管疾病的组合物和方法
公开(公告)号：WO2005117954A3
公开(公告)日：2006-10-12
申请号：PCT/US2005019800
申请日：2005-06-06
申请人： SCRIPPS RESEARCH INST , FRIEDLANDER MARTIN , AGUILAR HILDA EDITH , DORRELL MICHAEL I
发明人： FRIEDLANDER MARTIN , AGUILAR HILDA EDITH , DORRELL MICHAEL I
IPC分类号： A61K31/70 , A01N43/04 , A61K31/538 , A61K31/7072 , A61K38/19 , A61K38/47 , A61K38/51 , A61K45/06 , C07K1/00 , C07K14/00 , C07K17/00 , C12N9/00
CPC分类号： A61K31/7072 , A61K9/0048 , A61K31/538 , A61K38/00 , A61K45/06 , C12N9/93 , C12Y601/01002 , A61K2300/00
摘要： The present invention provides compositions and methods of treating neovascular diseases, such as a retinal neovascular diseases and tumors, by administering to a patient suffering from a neovascular disease or tumor a vascular development inhibiting amount of a combination of the angiogenesis suppressing drugs comprising an angiostatic fragment of tryptophanyl-tRNA synthetase (TrpRS) and at least one compound selected from the group consisting of a vascular endothelial growth factor (VEGF) signaling inhibitor and an integrin signaling inhibitor. Compositions for use in the methods include an admixture of an angiostatic fragment of tryptophanyl-tRNA synthetase (TrpRS) and at least one of a vascular endothelial growth factor (VEGF) signaling inhibitor and an integrin signaling inhibitor, together with a pharmaceutically acceptable excipient.
摘要翻译：本发明提供了通过对患有新生血管疾病或肿瘤的患者施用血管生成抑制药物的组合的血管生成抑制药物的组合物和方法，例如视网膜新生血管疾病和肿瘤，所述血管生成抑制药物包含血管生成抑制性片段的色氨酰-tRNA合成酶（TrpRS）和至少一种选自血管内皮生长因子（VEGF）信号传导抑制剂和整联蛋白信号传导抑制剂的化合物。用于该方法的组合物包括色氨酰-tRNA合成酶（TrpRS）的血管生成抑制片段和血管内皮生长因子（VEGF）信号传导抑制剂和整联蛋白信号传导抑制剂中的至少一种与药学上可接受的赋形剂的混合物。

8. 发明申请

WO2006104609A2 ISOLATED MYELOID-LIKE BONE MARROW CELL POPULATIONS AND METHODS OF TREATMENT THEREWITH 审中-公开
标题翻译：分离的MYELOID-likeBONE MARROW细胞群体及其治疗方法
公开(公告)号：WO2006104609A2
公开(公告)日：2006-10-05
申请号：PCT/US2006006411
申请日：2006-02-24
申请人： SCRIPPS RESEARCH INST , FRIEDLANDER MARTIN , RITTER MATTHEW R , MORENO STACEY K
发明人： FRIEDLANDER MARTIN , RITTER MATTHEW R , MORENO STACEY K
IPC分类号： C12N5/071 , A61K35/00 , C12N5/078
CPC分类号： C12N5/0647 , A61K2035/124 , C12N5/0692
摘要： The present invention provides an isolated myeloid-like bone marrow cell population comprising a majority of cells that are lineage negative, and which express both CD44 antigen and CD11b antigen. These cells have beneficial vasculotrophic and neurotrophic activity when intraocularly administered to the eye of a mammal, particularly a mammal suffering from an ocular degenerative disease. The myeloid-like bone marrow cells are isolated by treating bone marrow cells with an antibody against CD44 (hyaluronic acid receptor), against CD11b, or against both and using flow cytometry to positively select CD44 and/or CD11b expressing cells therefrom. The isolated myeloid-like bone marrow cells of the invention can be transfected with a gene encoding a therapeutically useful protein, for delivering the gene to the retina.
摘要翻译：本发明提供了分离的骨髓样骨髓细胞群，其包含谱系阴性的大多数细胞，并表达CD44抗原和CD11b抗原。当眼内施用于哺乳动物，特别是患有眼变性疾病的哺乳动物的眼睛时，这些细胞具有有益的血管营养和神经营养活性。通过用针对CD11b的抗CD44抗体（透明质酸受体）或针对CD11b的抗体处理骨髓细胞来分离骨髓样细胞，并使用流式细胞术从其中阳性选择表达CD44和/或CD11b的细胞。本发明的分离的骨髓样骨髓细胞可以用编码治疗有用的蛋白质的基因转染，用于将基因递送到视网膜。

9. 发明申请

WO2006031467A9 ISOLATED LINEAGE NEGATIVE HEMATOPOIETIC STEM CELLS AND METHODS OF TREATMENT THEREWITH 审中-公开
标题翻译：分离线阴性HEMATOPOIETIC干细胞及其治疗方法
公开(公告)号：WO2006031467A9
公开(公告)日：2006-06-01
申请号：PCT/US2005031304
申请日：2005-09-02
申请人： SCRIPPS RESEARCH INST , FRIEDLANDER MARTIN , OTANI ATSUSHI , DA SILVA KAREN , MORENO STACEY HANEKAMP
发明人： FRIEDLANDER MARTIN , OTANI ATSUSHI , DA SILVA KAREN , MORENO STACEY HANEKAMP
IPC分类号： A61K45/00 , C12N15/09 , A01N63/00 , A61K35/12 , A61K35/28 , A61K48/00 , A61P9/10 , A61P27/02 , C12N5/00 , C12N5/02 , C12N5/078 , C12N5/0789 , C12N5/10
CPC分类号： C12N5/0647 , A61K48/00 , A61K2035/124 , C12N5/0692
摘要： Isolated, mammalian, adult bone marrow-derived, lineage negative hematopoietic stem cell population (Lin HSCs) contain endothelial progenitor cells (ECPs) capable of rescuing retinal blood vessels and neuronal networks in the eye. Preferably at least about 20% of the cells in the isolated Lin HSCs express the cell surface antigen CD31. The isolated Lin HSC populations are useful for treatment of ocular vascular diseases and to ameliorate cone cell degeneration in the retina. In a preferred embodiment, the Lin HSCs are isolated by extracting bone marrow from an adult mammal; separating a plurality of monocytes from the bone marrow; labeling the monocytes with biotin-conjugated lineage panel antibodies to one or more lineage surface antigens; removing of monocytes that are positive for the lineage surface antigens from the plurality of monocytes, and recovering a Lin HSCs population containing EPCs. The isolated Lin HSCs also can be transfected with therapeutically useful genes. The treatment may be enhanced by stimulating proliferation of activated astrocytes in the retina using a laser.
摘要翻译：分离的，哺乳动物，成年骨髓来源的谱系负造血干细胞群（Lin HSCs）含有能够拯救眼睛中视网膜血管和神经元网络的内皮祖细胞（ECP）。优选地，分离的Lin HSC中至少约20％的细胞表达细胞表面抗原CD31。分离的Lin HSC群体可用于治疗眼血管疾病并改善视网膜中的锥细胞变性。在优选的实施方案中，通过从成年哺乳动物提取骨髓来分离Lin HSC; 从骨髓中分离多个单核细胞; 用与生物素缀合的谱系抗体对一种或多种谱系表面抗原标记单核细胞; 去除对来自多个单核细胞的谱系表面抗原呈阳性的单核细胞，以及回收含有EPCs的Lin HSC群体。分离的Lin HSC也可以用治疗有用的基因转染。可以通过使用激光刺激视网膜中活化的星形胶质细胞的增殖来增强治疗。

10. 发明申请

WO2004098499A3 HEMATOPOIETIC STEM CELLS AND METHODS OF TREATMENT OF NEOVASCULAR EYE DISEASES THEREWITH 审中-公开
标题翻译： HEMATOPOIETIC干细胞及其治疗新生血管性眼病的方法
公开(公告)号：WO2004098499A3
公开(公告)日：2005-10-06
申请号：PCT/US2004012989
申请日：2004-04-28
申请人： SCRIPPS RESEARCH INST , FRIEDLANDER MARTIN , OTANI ATSUSHI , DASILVA KAREN , HANEKAMP STACEY
发明人： FRIEDLANDER MARTIN , OTANI ATSUSHI , DASILVA KAREN , HANEKAMP STACEY
IPC分类号： C12N15/09 , A01N63/00 , A61K35/12 , A61K35/28 , A61K48/00 , A61P9/10 , A61P27/02 , C12N5/00 , C12N5/02 , C12N5/071 , C12N5/078 , C12N5/0789 , C12N5/10 , A01N65/00 , C12N5/08
CPC分类号： C12N5/0692 , A61K48/00 , A61K2035/124 , C12N5/0647
摘要： Isolated, mammalian, adult bone marrow-derived, lineage negative hematopoietic stem cell populations (Lin HSCs) contain endothelial progenitor cells (EPCs) capable of rescuing retinal blood vessels and neuronal networks in the eye. Preferably at least about 20% of the cells in the isolated Lin HSCs express the cell surface antigen CD31. The isolated Lin HSC populations are useful for treatment of ocular vascular diseases. In a preferred embodiment, the Lin HSCs are isolated by extracting bone marrow from an adult mammal; separating a plurality of monocytes from the bone marrow; labeling the monocytes with biotin-conjugated lineage panel antibodies to one or more lineage surface antigens; removing of monocytes that are positive for the lineage surface antigens from the plurality of monocytes, and recovering a Lin HSC population containing EPCs. Isolated Lin HSCs that have been transfected with therapeutically useful genes are also provided, and are useful for delivering genes to the eye for cell-based gene therapy. Methods of preparing isolated stem cell populations of the invention, and methods of treating ocular diseases and injury are also described.
摘要翻译：分离的，哺乳动物，成年骨髓来源的谱系负造血干细胞群（Lin < - > HSCs）含有能够拯救眼睛中视网膜血管和神经元网络的内皮祖细胞（EPCs）。优选地，分离的Lin HSC中至少约20％的细胞表达细胞表面抗原CD31。孤立的Lin < - > HSC群体可用于治疗眼血管疾病。在优选的实施方案中，通过从成年哺乳动物提取骨髓来分离Lin？从骨髓中分离多个单核细胞; 用与生物素缀合的谱系抗体对一种或多种谱系表面抗原标记单核细胞; 从多个单核细胞中除去对于谱系表面抗原呈阳性的单核细胞，以及回收含有EPC的Lin HSC群体。还提供已经用治疗有用的基因转染的分离的Lin < - > HSC，并且可用于将基因递送至眼睛用于基于细胞的基因治疗。还描述了制备本发明的分离的干细胞群体的方法，以及治疗眼部疾病和损伤的方法。

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