Forms of the angiogenic factor vascular endothelial cell...

Details Forms of the angiogenic factor vascular endothelial cell... Forms of the angiogenic factor vascular endothelial cell...

1999-02-04

2002-11-12

Priebe, Scott D. (Department: 1632)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S023100, C435S320100

Reexamination Certificate

active

06479654

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel forms of vascular endothelial growth factor genes and the novel proteins encoded by these genes. More particularly, the invention relates to novel forms of human VEGF-A. These novel forms of VEGF-A include VEGF-A
138
, VEGF-A
162
, and VEGF-A
182
. Such novel VEGF proteins may be used in the treatment of the cardiovascular system and its diseases through effects on anatomy, conduit function, and permeability, and more particularly in the treatment of cardiovascular disease by stimulating vascular cell proliferation using a growth factor, thereby stimulating endothelial cell growth and vascular permeability.
The invention also relates to nucleic acids encoding such novel VEGF proteins, cells, tissues and animals containing such nucleic acids; methods of treatment using such nucleic acids; and methods relating to all of the foregoing.
BACKGROUND OF THE INVENTION
Cardiovascular diseases are generally characterized by an impaired supply of blood to the heart or other target organs. Myocardial infarction (MI), commonly referred to as heart attacks, is a leading cause of mortality as 30% are fatal in the first months following the heart attack. Heart attacks result from narrowed or blocked coronary arteries in the heart which starves the heart of needed nutrients and oxygen. When the supply of blood to the heart is compromised, cells respond by generating compounds that induce the growth of new blood vessels so as to increase the supply of blood to the heart. These new blood vessels are called collateral blood vessels. The process by which new blood vessels are induced to grow out of the existing vasculature is termed angiogenesis, and the substances that are produced by cells to induce angiogenesis are the angiogenic factors.
Unfortunately, the body's natural angiogenic response is limited and often inadequate. For this reason, the discovery of angiogenic growth factors has lead to the emergence of an alternative therapeutic strategy which seeks to supplement the natural angiogenic response by supplying exogenous angiogenic substances.
Attempts have been made to stimulate angiogenesis by administering various growth factors. U.S. Pat. No. 5,318,957 to Cid et al. discloses a method of stimulating angiogenesis by administering haptoglobins (glyco-protein with two polypeptide chains linked by disulfide bonds). Intracoronary injection of a recombinant vector expressing human fibroblast growth factor-5 (FGF-5) (i.e., in vivo gene transfer) in an animal model resulted in successful amelioration of abnormalities in myocardial blood flow and function. (Giordano, F. J., et. al.
Nature Med
2, 534-539, 1996). Recombinant adenoviruses have also been used to express angiogenic growth factors in-vivo. These included acidic fibroblast growth factor (Muhlhauser, J., et. al.
Hum. Gene Ther.
6:1457-1465, 1995), and one of the VEGF forms, VEGF-A
165
(Muhlhauser, J., et. al.
Circ. Res.
77:1077-1086, 1995).
One of the responses of heart muscle cells to impaired blood supply involves activation of the gene encoding Vascular Endothelial Growth Factor (“VEGF”), also known as VEGF-A, (Banai, S., et. al.
Cardiovasc. Res.
28:1176-1179, 1994). VEGF-A is actually a family of angiogenic factors that induce the growth of new collateral blood vessels. These growth factors are specific angiogenic growth factors that have vaso-permeability activity and target endothelial (blood vessel-lining) cells almost exclusively. (Reviewed in Ferrara et al.,
Endocr. Rev.
13:18-32 (1992); Dvorak et al.,
Am. J. Pathol.
146:1029-39 (1995); Thomas,
J. Biol. Chem.
271:603-06 (1996)). Expression of the VEGF-A gene is linked in space and time to events of physiological angiogenesis, and deletion of the VEGF-A gene by way of targeted gene disruption in mice leads to embryonic death because the blood vessels do not develop. It is therefore the only known angiogenic growth factor that appears to function as a specific physiological regulator of angiogenesis.
When tested in cell culture, VEGF-A, and, because of its structure, likely VEGF-B, (VEGF's) are potently mitogenic (Gospodarowicz et al.,
Proc. Natl. Acad. Sci. USA
86:7311-15, 1989) and chemotactic (Favard et al.,
Biol. Cell
73:1-6, 1991). Additionally, VEGFs induce plasminogen activator, plasminogen activator inhibitor, and plasminogen activator receptor (Mandriota et al.,
J. Biol. Chem.
270:9709-16, 1995; Pepper et al., 181: 902-06, 1991), as well as collagenases (Unemori et al.,
J. Cell. Physiol.
153:557-62, 1992), enzyme systems that regulate invasion of growing capillaries into tissues. VEGFs also stimulate the formation of tube-like structures by endothelial cells, an in vitro example of angiogenesis (Nicosia et al.,
Am. J. Pathol.,
145:1023-29, 1994).
In vivo, VEGFs induce angiogenesis (Leung et al.,
Science
246:1306-09, 1989) and increase vascular permeability (Senger et al.,
Science
219:983-85, 1983). VEGFs are now known as important physiological regulators of capillary blood vessel formation. They are involved in the normal formation of new capillaries during organ growth, including fetal growth (Peters et al.,
Proc. Natl. Acad. Sci. USA
90:8915-19, 1991), tissue repair (Brown et al.,
J. Exp. Med.
176:1375-79, 1992), the menstrual cycle, and pregnancy (Jackson et al.,
Placenta
15:341-53, 1994; Cullinan & Koos,
Endocrinology
133:829-37, 1993; Kamat et al.,
Am. J. Pathol.
146:157-65, 1995). During fetal development, VEGFs appear to play an essential role in the de novo formation of blood vessels from blood islands (Risau & Flamme,
Ann. Rev. Cell. Dev. Biol.
11:73-92, 1995), as evidenced by abnormal blood vessel development and lethality in embryos lacking a single VEGF allele (Carmeliet et al.,
Nature
380:435-38, 1996). Moreover, VEGFs are implicated in the pathological blood vessel growth characteristic of many diseases, including solid tumors (Potgens et al.,
Biol. Chem. Hoppe-Seyler
376:57-70, 1995), retinopathies (Miller et al.,
Am. J. Pathol.
145:574-84, 1994; Aiello et al.,
N. Engl. J. Med.
331:1480-87, 1994; Adamis et al.,
Am. J. Ophthalmol.
118:445-50, 1994), psoriasis (Detmar et al.,
J. Exp. Med.
180:1141-46, 1994), and rheumatoid arthritis (Fava et al.,
J. Exp. Med.
180:141-46, 1994).
VEGF expression is regulated by hormones (Schweiki et al.,
J. Clin. Invest.
91:2235-43, 1993) growth factors (Thomas,
J. Biol. Chem.
271:603-06, 1996), and by hypoxia (Schweiki et al.,
Nature
359:843-45, 1992, Levy et al.,
J. Biol. Chem.
271:2746-53, 1996). Upregulation of VEGFs by hypoxic conditions is of particular importance as a compensatory mechanism by which tissues increase oxygenation through induction of additional capillary vessel formation and resulting increased blood flow. This mechanism is thought to contribute to pathological angiogenesis in tumors and in retinopathies. However, upregulation of VEGF expression after hypoxia is also essential in tissue repair, e.g., in dermal wound healing (Frank et al.,
J. Biol. Chem.
270:12607-613, 1995), and in coronary ischemia (Banai et al.,
Cardiovasc. Res.
28:1176-79, 1994; Hashimoto et al.,
Am. J. Physiol.
267:H1948-H1954, 1994).
Using the rabbit chronic limb ischemia model, it has been shown that repeated intramuscular injection or a single intra-arterial bolus of VEGF-A can augment collateral blood vessel formation as evidenced by blood flow measurement in the ischemic hindlimb (Pu, et al.,
Circulation
88:208-15, 1993; Bauters et al.,
Am. J. Physiol.
267:HI263-71, 1994; Takeshita et al.,
Circulation
90 [part 2], II-228-34, 1994; Bauters et al.,
J. Vasc. Surg.
21:314-25, 1995; Bauters et al.,
Circulation
91:2802-09, 1995; Takeshita et al.,
J. Clin. Invest.
93:662-70, 1994). In this model, VEGF has also been shown to act synergistically with basic FGF to ameliorate ischemia (Asahara et al.,
Circulation
92:[suppl 2], II-365-71, 1995). VEGF was also reported to accelerate the repair of balloon-injured rat carotid artery endothelium while at the same time in

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