Compositions and methods for modulating vascularization

Details Compositions and methods for modulating vascularization Compositions and methods for modulating vascularization

1999-03-09

2004-01-13

Guzo, David (Department: 1636)

Drug, bio-affecting and body treating compositions

Whole live micro-organism, cell, or virus containing

Animal or plant cell

C424S085100, C514S04400A, C435S325000, C435S355000, C435S372000, C435S455000

Reexamination Certificate

active

06676937

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to methods for modulating vascularization particularly in a mammal. In one aspect, methods are provided for modulating vascularization that includes administrating to the mammal an effective amount of granulocyte macrophage-colony stimulating factor (GM-CSF). Further provided are methods for treating or detecting damaged blood vessels in the mammal. The invention has a wide spectrum of useful applications including inducing formation of new blood vessels in the mammal.
BACKGROUND OF THE INVENTION
There is nearly universal recognition that blood vessels help supply oxygen and nutrients to living tissues. Blood vessels also facilitate removal of waste products. Blood vessels are renewed by a process termed “angiogenesis”. See generally Folkman and Shing,
J. Biol. Chem
. 267 (16), 10931-10934 (1992).
Angiogenesis is understood to be important for the well-being of most mammals. As an illustration, angiogenesis has been disclosed as being an essential process for reproduction, development and wound repair.
There have been reports that inappropriate angiogenesis can have severe consequences. For example, it has been disclosed that solid tumor growth is facilitated by vascularization. There is broad support for the concept that mammals must regulate angiogenesis extensively.
There has been much attention directed to understanding how angiogeneis is controlled. In particular, angiogenesis is believed to begin with the degradation of the basement membrane by proteases secreted from endothelial cells (EC) activated by mitogens, e.g., vascular endothelial growth factor (ie. VEGF-1), basic fibroblast growth factor (bFGF) and/or others. The cells migrate and proliferate, leading to the formation of solid endothelial cell sprouts into the stromal space, then, vascular loops are formed and capillary tubes develop with formation of tight junctions and deposition of new basement membrane.
In adults, it has been disclosed that the proliferation rate of endothelial cells is typically low, compared to other cell types in the body. The turnover time of these cells can exceed one thousand days. Physiological exceptions in which angiogenesis results in rapid proliferation occurs under tight regulation are found in the female reproduction system and during wound healing. It has been reported that the rate of angiogenesis involves a change in the local equilibrium between positive and negative regulators of the growth of microvessels.
Abnormal angiogenesis is thought to occur when the body loses its control of angiogenesis, resulting in either excessive or insufficient blood vessel growth. For instance, conditions such as ulcers, strokes, and heart attacks may result from the absence of angiogenesis normally required for natural healing. In contrast, excessive blood vessel proliferation can facilitate tumor growth, blindness, psoriasis, rheumatoid arthritis, as well as other medical conditions.
The therapeutic implications of angiogenic growth factors were first described by Folkman and colleagues over two decades ago (Folkman,
N. Engl. J. Med
., 85:1182-1186 (1971)). Recent work has established the feasibility of using recombinant angiogenic growth factors, such as fibroblast growth factor (FGF) family (Yanagisawa-Miwa, et al.,
Science
, 257:1401-1403 (1992) and Baffour, et al.,
J Vasc Surg
, 16:181-91 (1992)), endothelial cell growth factor (ECGF)(Pu, et al.,
J Surg Res
, 54:575-83 (1993)), and vascular endothelial growth factor (VEGF-1) to expedite and/or augment collateral artery development in animal models of myocardial and hindlimb ischemia (Takeshita, et al., Circulation, 90:228-234 (1994) and Takeshita, et al.,
J Clin Invest
, 93:662-70 (1-994)).
The feasibility of using gene therapy to enhance angiogenesis has received recognition. For example, there have been reports that angiogenesis can facilitate treatment of ischemia in a rabbit model and in human clinical trials. Particular success has been achieved using VEGF-1 administered as a balloon gene delivery system. Successful transfer and sustained expression of the VEGF-1 gene in the vessel wall subsequently augmented neovascularization in the ischemic limb (Takeshita, et al.,
Laboratory Investigation
, 75:487-502 (1996); Isner, et al.,
Lancet
, 348:370 (1996)). In addition, it has been reported that direct intramuscular injection of DNA encoding VEGF-1 into ischemic tissue induces angiogenesis, providing the ischemic tissue with increased blood vessels (Tsurumi et al.,
Circulation
, 94(12):3281-3290 (1996)).
Alternative methods for promoting angiogenesis are desirable for a number of reasons. For example, it is believed that native endothelial progenitor cell (EPC) number and/or viability decreases over time. Thus, in certain patient populations, e.g., the elderly, EPCs capable of responding to angiogenic proteins may be limited. Also, such patients may not respond well to conventional therapeutic approaches.
There have been reports that at least some of these problems can be reduced by administering isolated EPCs to patients and especially those undergoing treatment for ischemic disease. However, this suggestion is believed to be prohibitively expensive as it can require isolation and maintenance of patient cells. Moreover, handling of patient cells can pose a significant health risk to both the patient and attending personnel in some circumstances.
Granulocyte macrophage colony stimulating factor (GM-CSF) has been shown to exert a regulatory effect on granulocyte-committed progenitor cells to increase circulating granulocyte levels (Gasson, J. C.,
Blood
77:113 1 (1991). In particular, GM-CSF acts as a growth factor for granulocyte, monocyte and eosinophil progenitors.
Administration of GM-CSF to human and non-human primates results in increased numbers of circulating neutrophils, as well as eosinophils, monocytes and lymphocytes. Accordingly, GM-CSF is believed to be particularly useful in accelerating recovery from neutropenia in patients subjected to radiation or chemotherapy, or following bone marrow transplantation. In addition, although GM-CSF is less potent than other cytokines, e.g., FGF, in promoting EC proliferation, GM-CSF activates a fully migrating phenotype. (Bussolino, et al.,
J. Clin. Invent
., 87:986 (1991).
Accordingly, it would be desirable to have methods for modulating vascularization in a mammal and especially a human patient. It would be particularly desirable to have methods that increase EPC mobilization and neovascularization (formation of new blood vessels) in the patient that do not require isolation of EPC cells.
SUMMARY OF THE INVENTION
The present invention generally relates to methods for modulating vascularization in a mammal. In one aspect, the invention provides methods for increasing vascularization that includes administrating to the mammal an effective amount of a vascularization modulating agent, such as granulocyte macrophage-colony stimulating factor (GM-CSF), VEGF, Steel factor (SLF, also known as Stem cell factor (SCF)), stromal cell-derived factor (SDF-1), granulocyte-colony stimulating factor (G-CSF), HGF, Angiopoietin-1, Angiopoietin-2, M-CSF, b-FGF, and FLT-3 ligand, and effective fragment thereof, or DNA coding for such vascularization modulating agents. Such materials have sometimes previously been described as “hematopoietic factors.” and/or “hematopoietic proteins.” Disclosure relating to these and other hematopoietic factors can be found in Kim, C. H. and Broxmeyer, H. E. (1998)
Blood
, 91:100; Turner, M. L. and Sweetenham, J. W., Br. J.
Haematol
. (1996) 94:592; Aiuuti, A. et al. (1997)
J. Exp. Med
. 185:111; Bleul, C. et al. (1996)
J. Exp. Med
. 184:1101; Sudo, Y. et al. (1 997)
Blood
, 89: 3166; as well as references disclosed therein. Prior to the present invention, it was not kown that GM-CSF or other hematopoietic factors could potentiate endothelial progenitor cells, or modulate neovascularization as described herein.
Alternatively, instead of the proteins themselves or effective fragments thereof, the DNA cod

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