公开(公告)号：US20060003933A1

公开(公告)日：2006-01-05

申请号：US11145587

申请日：2005-06-06

Applicant: Martin Friedlander ,  Hilda Aguilar ,  Michael Dorrell

Inventor： Martin Friedlander ,  Hilda Aguilar ,  Michael Dorrell

IPC: A61K38/47 ,  A61K31/7072 ,  A61K31/538

CPC classification number: A61K31/7072 ,  A61K9/0048 ,  A61K31/538 ,  A61K38/00 ,  A61K45/06 ,  C12N9/93 ,  C12Y601/01002 ,  A61K2300/00

Abstract: 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.

公开(公告)号：US20050004013A1

公开(公告)日：2005-01-06

申请号：US10836289

申请日：2004-04-30

Applicant: Martin Friedlander ,  Michael Dorrell

Inventor： Martin Friedlander ,  Michael Dorrell

IPC: A61K38/00 ,  A61K38/06 ,  A61K38/08 ,  A61K38/10 ,  A61K38/12 ,  C07K20060101 ,  C07K14/705

CPC classification number: C07K14/705 ,  A61K38/00

Abstract: 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 Ile-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.

Abstract translation: 可用作哺乳动物R-钙粘蛋白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Ile-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-钙粘蛋白介导的细胞粘附和抑制视网膜血管生成。

公开(公告)号：US20070207154A1

公开(公告)日：2007-09-06

申请号：US11578338

申请日：2005-04-15

Applicant: Martin Friedlander ,  Wolfram Ruf ,  Michael Dorrell ,  Mattias Belting

Inventor： Martin Friedlander ,  Wolfram Ruf ,  Michael Dorrell ,  Mattias Belting

IPC: A61K39/395 ,  A61K38/36

CPC classification number: C12N15/86 ,  A61K38/17 ,  A61K38/4846 ,  A61K48/00 ,  A61K2039/505 ,  C07K16/36 ,  C12N2710/10343

Abstract: 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 Ser258 of the cytoplasmic tail of TF). In a preferred method pathological 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.

Abstract translation: 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，通过给予患有病理性新生血管形成的哺乳动物治疗有效量的PAR信号通路抑制剂来治疗病理学。 优选地，哺乳动物是人。

公开(公告)号：US07931891B2

公开(公告)日：2011-04-26

申请号：US11884958

申请日：2006-02-24

Applicant: Martin Friedlander ,  Matthew R. Ritter ,  Stacey K. Moreno

Inventor： Martin Friedlander ,  Matthew R. Ritter ,  Stacey K. Moreno

IPC: A01N65/00 ,  A01N1/02 ,  A01K48/00

CPC classification number: C12N5/0647 ,  A61K2035/124 ,  C12N5/0692

Abstract: The present invention provides an isolated myeloid-like cell population comprising a majority of cells that are lineage negative, and which express both CD44 antigen, CD11b antigen, and hypoxia inducible factor 1 α (HIF-1 α). 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 cells are isolated by treating bone marrow cells, peripheral blood cells or umbilical cord cells with an antibody against CD44 (hyaluronic acid receptor), against CD11b, CD14, CD33, or against a combination thereof 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.

Abstract translation: 本发明提供了分离的骨髓样细胞群，其包含谱系阴性的大部分细胞，并表达CD44抗原，CD11b抗原和缺氧诱导因子1α（HIF-1α）。 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CD44（透明质酸受体）的抗体对CD11b，CD14，CD33或其组合处理骨髓细胞，外周血细胞或脐带细胞来分离骨髓样细胞，并使用流式细胞术积极选择 CD44和/或CD11b表达细胞。 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，用于将该基因递送至视网膜。

公开(公告)号：US20070116685A1

公开(公告)日：2007-05-24

申请号：US11643571

申请日：2006-12-20

Applicant: Martin Friedlander ,  Atsushi Otani ,  Karen Silva

Inventor： Martin Friedlander ,  Atsushi Otani ,  Karen Silva

IPC: A61K35/14 ,  C12N5/06 ,  C12N5/08

CPC classification number: C12N5/0692 ,  A61K48/00 ,  A61K2035/124 ,  C12N5/0647

Abstract: Isolated, mammalian, bone marrow-derived, hematopoietic stem cell populations contain endothelial progenitor cells (EPC) capable of forming retinal blood vessels. At least about 50% of the cells in the isolated cell population express CD31 and c-kit. Up to about 8% of the cells can express Sca-1, and up to about 4% of the cells can express Flk-1/KDR. The cells can incorporate into the vasculature of the retina when intravitreally injected into the eye, and can thereby stabilize or rebuilt diseased or abnormal retinal blood vessels.

Abstract translation: 分离的，哺乳动物，骨髓来源的造血干细胞群含有能够形成视网膜血管的内皮祖细胞（EPC）。 分离的细胞群中至少约50％的细胞表达CD31和c-kit。 高达约8％的细胞可以表达Sca-1，最多约4％的细胞可以表达Flk-1 / KDR。 当玻璃体内注射到眼睛中时，细胞可以并入视网膜的脉管系统中，从而可以稳定或重建患病或异常的视网膜血管。

公开(公告)号：US20060165703A1

公开(公告)日：2006-07-27

申请号：US11290896

申请日：2005-11-29

Applicant: Peter Brooks ,  David Cheresh ,  Martin Friedlander

Inventor： Peter Brooks ,  David Cheresh ,  Martin Friedlander

IPC: A61K39/395 ,  A61K39/00 ,  C07K14/82 ,  C07K16/30

CPC classification number: A61K38/57 ,  A61K2039/505 ,  C07K16/2839 ,  C07K16/2848 ,  C07K2317/76

Abstract: The present invention describes methods for inhibiting angiogenesis in tissues using vitronectin αvβ5 antagonists. The αvβ5-mediated angiogenesis is correlated with exposure to cytokines including vascular endothelial growth factor, transforming growth factor-α and epidermal growth factor. Inhibition of αvβ5-mediated angiogenesis is particularly preferred in vascular endothelial ocular neovascular diseases, in tumor growth and in inflammatory conditions, using therapeutic compositions containing αvβ5 antagonists.

Abstract translation: 本发明描述了使用玻连蛋白α5β5拮抗剂抑制组织中血管生成的方法。 α-β5介导的血管发生与包括血管内皮生长因子，转化生长因子-α和表皮生长因子在内的细胞因子的暴露相关。 使用含有αV的治疗组合物，在血管内皮细胞新生血管疾病，肿瘤生长和炎性病症中，对α5β5介导的血管生成的抑制是特别优选的 5β拮抗剂。

公开(公告)号：US20060104963A1

公开(公告)日：2006-05-18

申请号：US11168130

申请日：2005-06-28

Applicant: Martin Friedlander ,  Atsushi Otani ,  Karen Silva ,  Stacey Moreno

Inventor： Martin Friedlander ,  Atsushi Otani ,  Karen Silva ,  Stacey Moreno

IPC: A61K48/00 ,  C12N5/06 ,  C12N5/08

CPC classification number: C12N5/0647 ,  A61K38/00 ,  A61K48/00 ,  A61K2035/124 ,  C12N5/0692

Abstract: Transfected, 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 express the cell surface antigen CD31. The transfected stem cells express an antiangiogenic fragment of tryptophanyl tRNA synthetase (TrpRS). The transfected 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− HSC population containing EPCs. The treatment may be enhanced by stimulating proliferation of activated astrocytes in the retina using a laser.

Abstract translation: 转染的哺乳动物，成年骨髓来源的血清造血干细胞群体（含有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，至少约20％的细胞表达细胞表面抗原CD31。 转染的干细胞表达色氨酸tRNA合成酶（TrpRS）的抗血管生成片段。 转染的HSH-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骨髓间充质干细胞; 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EPCs的LINC-HSC群体。 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。

公开(公告)号：US08796237B2

公开(公告)日：2014-08-05

申请号：US13229866

申请日：2011-09-12

Applicant: Paul Schimmel ,  Keisuke Wakasugi ,  Martin Friedlander

Inventor： Paul Schimmel ,  Keisuke Wakasugi ,  Martin Friedlander

IPC: C07H21/04 ,  C07K14/515

CPC classification number: C12N9/93 ,  A61K38/00 ,  C07H21/04 ,  C07K14/515 ,  C07K14/521 ,  C12Y601/01002 ,  Y10S435/975

Abstract: The invention provides an isolated nucleic acid encoding a polypeptide capable of inhibiting angiogenesis or neovascularization, wherein the nucleic acid comprises a first polynucleotide sequence comprising a coding sequence at least 95 percent identical to a sequence selected from the group consisting of a polynucleotide SEQ ID NO:6, a polynucleotide that encodes a polypeptide of SEQ ID NO:12, and a polynucleotide that encodes a fragment of the polypeptide of SEQ ID NO:12; and wherein the nucleic acid does not encode for the amino acid sequence of amino acids 71-93 of SEQ ID NO:1. Pharmaceutical compositions, vectors, and methods for inhibiting neovascularization or angiogenesis comprising or utilizing the nucleic acids also are provided.

Abstract translation: 本发明提供了编码能够抑制血管生成或新生血管形成的多肽的分离的核酸，其中所述核酸包含第一多核苷酸序列，所述第一多核苷酸序列包含与选自多核苷酸SEQ ID NO： 6，编码SEQ ID NO：12的多肽的多核苷酸和编码SEQ ID NO：12的多肽的片段的多核苷酸; 并且其中所述核酸不编码SEQ ID NO：1的氨基酸71-93的氨基酸序列。 还提供了用于抑制新生血管形成或血管发生的药物组合物，载体和方法，其包含或利用核酸。

公开(公告)号：US08017593B2

公开(公告)日：2011-09-13

申请号：US12319822

申请日：2009-01-13

Applicant: Paul Schimmel ,  Keisuke Wakasugi ,  Martin Friedlander

Inventor： Paul Schimmel ,  Keisuke Wakasugi ,  Martin Friedlander

IPC: A61K48/00

CPC classification number: C12N9/93 ,  A61K38/00 ,  C07H21/04 ,  C07K14/515 ,  C07K14/521 ,  C12Y601/01002 ,  Y10S435/975

Abstract: The invention provides a method for inhibiting ocular neovascularization in a patient. The method comprises administering to a patient an ocular neovascularization inhibiting amount of a water-soluble polypeptide selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 7, and an ocular neovascularization inhibiting fragment thereof, which includes at least one of amino acid residue signature sequences HVGH (SEQ ID NO:10) and KMSAS (SEQ ID NO:11). A method for assaying the angiogenesis inhibiting activity of a composition is also provided.

Abstract translation: 本发明提供一种抑制患者眼新生血管形成的方法。 该方法包括向患者施用眼新生血管形成抑制量的选自SEQ ID NO：12，SEQ ID NO：7的水溶性多肽和其新生血管形成抑制片段，其包括至少一种 氨基酸残基特征序列HVGH（SEQ ID NO：10）和KMSAS（SEQ ID NO：11）。 还提供了用于测定组合物的血管发生抑制活性的方法。

公开(公告)号：US07645736B2

公开(公告)日：2010-01-12

申请号：US11510596

申请日：2006-08-28

Applicant: Hans-Markus Bender ,  Jutta Haunschild ,  Ulrich Lang ,  Matthias Wiesner ,  Martin Friedlander

Inventor： Hans-Markus Bender ,  Jutta Haunschild ,  Ulrich Lang ,  Matthias Wiesner ,  Martin Friedlander

IPC: A61K38/00

CPC classification number: A61K31/538 ,  A61K31/335 ,  A61K31/351 ,  A61K31/38 ,  A61K31/395 ,  A61K31/405 ,  A61K38/12

Abstract: Methods for the treatment of a disease of the eye of a patient comprising injecting into the vitreous body of the eye a composition comprising a therapeutically effective amount of an αvβ3 and/or αvβ5 inhibitor sufficient to inhibit angiogenesis and inhibit neovascularization in the treated eye. The αvβ3 and/or αvβ5 inhibitor being a compound of formula II: as defined herein or a physiologically acceptable salt thereof.

Abstract translation: 用于治疗患者眼睛疾病的方法，包括将眼睛的玻璃体注入含有治疗有效量的足以抑制血管发生并抑制治疗眼睛新生血管形成的α噬菌体3和/或甲泼尼布5抑制剂的组合物。 阿尔法派菌素3和/或阿尔泊肽5抑制剂是式II化合物：如本文所定义或其生理上可接受的盐。