CA2322559A1 - Compositions and methods for modulating vascularization - Google Patents

Compositions and methods for modulating vascularization Download PDF

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Publication number
CA2322559A1
CA2322559A1 CA002322559A CA2322559A CA2322559A1 CA 2322559 A1 CA2322559 A1 CA 2322559A1 CA 002322559 A CA002322559 A CA 002322559A CA 2322559 A CA2322559 A CA 2322559A CA 2322559 A1 CA2322559 A1 CA 2322559A1
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Prior art keywords
mammal
csf
growth factor
epc
sufficient
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CA002322559A
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French (fr)
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CA2322559C (en
Inventor
Jeffrey M. Isner
Takayuki Asahara
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St Elizabeths Medical Center of Boston Inc
Original Assignee
St. Elizabeth's Medical Center
Jeffrey M. Isner
Takayuki Asahara
Caritas St. Elizabeth's Medical Center Of Boston, Inc.
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Application filed by St. Elizabeth's Medical Center, Jeffrey M. Isner, Takayuki Asahara, Caritas St. Elizabeth's Medical Center Of Boston, Inc. filed Critical St. Elizabeth's Medical Center
Publication of CA2322559A1 publication Critical patent/CA2322559A1/en
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Publication of CA2322559C publication Critical patent/CA2322559C/en
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56966—Animal cells
    • G01N33/56972—White blood cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/44—Vessels; Vascular smooth muscle cells; Endothelial cells; Endothelial progenitor cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1858—Platelet-derived growth factor [PDGF]
    • A61K38/1866—Vascular endothelial growth factor [VEGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/193—Colony stimulating factors [CSF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Immunology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cell Biology (AREA)
  • Zoology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Vascular Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biotechnology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Virology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Microbiology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Food Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The present invention generally provides methods for modulating formation of new blood vessels. In one embodiment, the methods include administering to a mammal an effective amount of granulocyte macrophage-colony stimulating factor (GM-CSF) sufficient to form the new blood vessels. Additionally provided are methods for preventing or reducing the severity of blood vessel damage in a mammal which methods preferably include administering to the mammal an effective amount of GM-CSF. Provided also as part of this invention are pharmaceutical products and kits for inducing formation of new blood vessels in the mammal.

Claims (48)

What is claimed is:
1. A method for inducing formation of new blood vessels in a mammal. wherein the method comprises administering to the mammal an effective amount of a vascularization modulating agent sufficient to form the new blood vessels in the mammal.
1A. The method of claim 1, wherein the vascularization modulating anent is GM-CSF, M-CSF, b-FGF, SCF, SDF-1, G-CSF, HGF, Angiopoietin-1 Angiopoietin-2, FLT-3 ligand. or an effective fragment thereof.
2. The method of claim 1, wherein the vascularization modulating went is GM-CSF, and amount of the GM-CSF administered to the mammal is sufficient to increase frequency of endothelial progenitor cells (EPC) in the mammal.
3. The method of claim 2, wherein the increase in frequency of the EPC is at least about 20% as determined by a standard EPC isolation assay.
4. The method of claim 1, wherein the amount of vascularization modulating went administered to the mammal is sufficient to increase EPC
differentiation in the mammal.
5. The method of claim 4, wherein the increase in EPC
differentiation is at least about 20% as determined by a standard EPC culture assay.
6. The method of claim 1, wherein the amount of vascularization modulating agent administered to the mammal is sufficient to increase blood vessel length in the mammal.
7. The method of claim 6, wherein the increase in blood vessel length is at least about 5% as determined by a standard blood vessel length assay.
8. The method of claim 6. wherein the amount of vascularization modulating agent administered to the mammal is further sufficient to increase blood vessel diameter in the mammal.
9. The method of claim 9, wherein the increase in blood vessel diameter is at least about 5,% as determined by a standard blood vessel diameter assay.
10. The method of claim l, wherein the amount of vascularization modulating agent administered to the mammal is sufficient to increase EPC
differentiation following tissue ischemia.
11. The method of claim 10, wherein the increase in EPC
differentiation is at least about 20% as determined by a standard hindlimb ischemia assay.
12. The method of claim 1, wherein the amount of administered vascularization modulating went is sufficient to increase neovascularization by at least about 5% as determined by a standard cornea micropocket assay. .
13. The method of claim 1, wherein the amount of administered vascularization modulating agent is sufficient to increase EPC bone marrow derived EPC incorporation into foci.
14. The method of claim 13, wherein the increase in EPC bone marrow derived EPC incorporation into foci is at least about 20% as determined by a standard rodent bone marrow (BM) transplantation model.
15. The method of claim l, wherein the mammal has, is suspected of having, or will have ischemic tissue.
16. The method of claim l5. wherein the ischemic tissue is associated with an ischemic vascular disease.
17. The method of claim 15, wherein the ischemic tissue comprises tissue from a limb, graft, or organ.
18. The method of claim 15. wherein the tissue is associated with the circulatory system or the central nervous system.
19. The method of claim 15, wherein the tissue is heart or brain tissue.
20. The method of claim l, wherein the is co-administered with at least one angiogenic protein.
21. The method of claim 20, wherein the angiogenic protein is an endothelial cell mitogen.
22. The method of claim 20, wherein the angiogenic protein is acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), vascular. endothelial growth factor (VEGF-1), epidermal growth factor (EGF), transforming growth factor .alpha. and .beta. (TGF-.alpha. and TFG-.beta.), platelet-derived endothelial growth factor (PD-ECGF), platelet-derived growth factor (PDGF), tumor necrosis factor .alpha. (TNF-.alpha.), hepatocyte Growth factor (HGF), insulin like growth factor (IGF), erythropoietin, colony stimulating factor (CSF), macrophage-CSF (M-CSF), angiopoetin-1 (Angl) or nitric oxidesynthase (NOS); or a fragment thereof.
23. The method of claim 22, wherein the protein is one of VEGF-B, VEGF-C, VEGF-2. VEGF-3; or an effective fragment thereof
24. A method for preventing or reducing the severity of blood vessel damage in a mammal. wherein the method comprises administering to the mammal an effective amount of granulocyte macrophage-colony stimulating factor (GM-CSF); and exposing the mammal to conditions conducive to damaging the blood vessels, the amount of GM-CSF being sufficient to prevent or reduce the severity of the blood vessel damage in the mammal.
25. The method of claim 24, wherein the conditions conducive to the blood vessel damage are an invasive manipulation or ischemia.
26. The method of claim 25, wherein the invasive manipulation is surgery.
27. The method of claim 25, wherein the ischemic is associated with at least one of infection, trauma, graft rejection. cerebrovascular ischemia, renal ischemia. pulmonary ischemia, limb ischemia, ischemic cardiomyopathy, or myocardial ischemia.
28. The method of claim 24, wherein the GM-CSF is administered to the mammal at least about 12 hours before exposing the mammal to the conditions conducive to damaging the blood vessels.
29. The method of claim 28, wherein the GM-CSF is administered to the mammal between from about 1 to 10 days before exposing the mammal to the conditions conducive to damaging the blood vessels.
30. The method of claim 28, wherein the method further comprises administering the GM-CSF to the mammal following the exposure to the conditions conducive to damaging the blood vessels.
31. A method for treating ischemic tissue in a mammal in need of such treatment, wherein the method comprises:
a) isolating endothelial progenitor cells (EPCs) from the mammal, b) contacting the isolated EPCs with an amount of an angiogenic protein sufficient to induce proliferation of the EPCs; and c) administering the proliferated EPCs to the mammal in an amount sufficient to treat the ischemic tissue.
32. The method of claim 31, wherein the EPCs have at least one of the following markers: CD34+, flk-1+ or tie-2+.
33. The method of claim 31, wherein the ischemic tissue comprises injured blood vessels.
-34. The method of claim 33, wherein the blood vessels are injured by an invasive manipulation.
35. The method of claim 34, wherein the invasive manipulation is balloon angioplasry, or deployment of a stent or catheter.
36. The method of claim 35, wherein the stem is an endovascular stem.
37. The method of claim 31 further comprising co-administering at least one angiogenic protein.
38. The method of claim 37, wherein the angiogenic protein is an endothelial cell mitogen or a nucleic acid encoding the endothelial cell mitogen.
39. The method of claim 38, wherein the angiogenic protein is acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF-1), epidermal growth factor {EGF), transforming growth factor .alpha. and .beta. (TGF-.alpha. and TFG-.beta.), platelet-derived endothelial growth factor (PD-ECGF), platelet-derived growth factor (PDGF), tumor necrosis factor .alpha. (TNF-.alpha.), hepatocyte growth factor (HGF), insulin like growth factor {IGF), erythropoietin, colony stimulating factor (CSF), macrophage-CSF (M-CSF), angiopoetin-1 (Angl) or nitric oxidesynthase (NOS); or a fragment thereof.
40. The method of claim 39, wherein the protein is one of VEGF-B, VEGF-C. VEGF-2, VEGF-3; or a fragment thereof.
41. A method for detecting presence of tissue damage in a mammal, wherein the method comprises contacting the mammal with a detectably-labeled population of endothelical progenitor cells (EPCs); and detecting the .
labeled cells at or near the site of the tissue damage in the mammal.
42. The method of claim 41. wherein the tissue damage is ischemia or an ischemic vascular disease.
43. A pharmaceutical product for inducing neovascularization in a mammal. wherein the product comprises isolated endothelial progenitor cells (EPCs) and is formulated to be physiologically acceptable to a mammal.
44. The pharmaceutical product of claim 43, wherein the product is sterile and further comprises at least one angiogenic protein or nucleic acid encoding the protein.
45. A kit for the systemic introduction of a isolated endothelial progenitor cells (EPCs), wherein the kit comprises the isolated EPCs and optionally at least one angiogenic protein or nucleic acid encoding same, the kit further optionally comprising a pharmacologically acceptable carrier solution, nucleic acid or mitogen, means for delivering the EPCs and directions for using the kit.
46. The kit of claim 45, wherein the means for delivering the EPCs is a stent, catheter or syringe.
47. A method for enhancing endothelial progenitor cell (EPC) mobilization in a mammal, wherein the method comprises administering an effective amount of at least one hematopoietic factor sufficient to enhance the EPC mobilization in the mammal.
48. The method of claim 47 further comprising co-administering to the mammal an effective amount of one or more of: granulocyte macrophage-colony stimulating factor (GM-CSF); at least one angiogenic protein; or an effective fragment thereof.
CA2322559A 1998-03-09 1999-03-09 Compositions and methods for modulating vascularization Expired - Fee Related CA2322559C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US7726298P 1998-03-09 1998-03-09
US60/077,262 1998-03-09
PCT/US1999/005130 WO1999045775A1 (en) 1998-03-09 1999-03-09 Compositions and methods for modulating vascularization

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CA2322559A1 true CA2322559A1 (en) 1999-09-16
CA2322559C CA2322559C (en) 2012-07-17

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EP (1) EP1061800A4 (en)
JP (2) JP2002506008A (en)
AU (1) AU766238B2 (en)
CA (1) CA2322559C (en)
WO (1) WO1999045775A1 (en)

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Publication number Publication date
WO1999045775A1 (en) 1999-09-16
EP1061800A1 (en) 2000-12-27
AU766238B2 (en) 2003-10-09
JP2002506008A (en) 2002-02-26
EP1061800A4 (en) 2004-10-06
AU3073799A (en) 1999-09-27
CA2322559C (en) 2012-07-17
JP2010265301A (en) 2010-11-25

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