Compositions and methods for the diagnosis and treatment of disorders involving angiogenesis

Abstract

Compositions and methods are disclosed for stimulating or inhibiting angiogeniesis and/or cardiovascularization in mammals, including humans. Pharmaceutical compositions are based on polypeptides or antagonists thereto that have been identified for one or more of these uses. Disorders that can be diagnosed, prevented, or treated by the compositions herein include trauma such as wounds, various cancers, and disorders of the vessels including atherosclerosis and cardiac hypertrophy. In addition, the present invention is directed to novel polypeptides and to nucleic acid molecules encoding those polypeptides. Also provided herein are vectors and host cells comprising those nucleic acid sequences, chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, antibodies which bind to the polypeptides of the present invention and to methods for producing the polypeptides of the present invention.

Description

1. FIELD OF THE INVENTION[0001] The present invention relates to compositions and methods useful for the modulation (e.g., promotion or inhibition) of angiogenesis and / or cardiovascularization in mammals in need of such biological effect. The present invention further relates to the diagnosis and treatment of disorders involving angiogenesis (e.g., cardiovascular as well as oncological disorders).2. BACKGROUND OF THE INVENTION2.1. Angiogenesis[0002] Angiogenesis, defined as the growth or sprouting of new blood vessels from existing vessels, is a complex process that primarily occurs during embryonic development. Under normal physiological conditions in adults, angiogenesis takes place only in very restricted situations such as hair growth and wounding healing (Auerbach, W. and Auerbach, R., 1994, Pharmacol Ther 63(3):265-3 11; Ribatti et al., 1991, Haematologica 76(4):3 11-20; Risau, 1997, Nature 386(6626):67 1-4). Unregulated angiogenesis has gradually been recognized to be respons...

AI Technical Summary

Benefits of technology

0103] In yet other embodiments, the invention provides oligonucleotide probes useful for isolating genomic and cDNA nucleotide sequences or as antisense probes, wherein those probes may be derived from any of the above or below described nucleotide sequences.

Problems solved by technology

CHF is a syndrome characterized by left ventricular dysfunction, reduced exercise tolerance, impaired quality of life, and markedly shortened life expectancy.

The sine qua non of heart failure is an inability of the heart to pump blood at a rate sufficient to meet the metabolic needs of the body's tissues (in other words, there is insufficient cardiac output).

As noted below, angiotensin II may also have directly deleterious effects on the heart by promoting myocyte necrosis (impairing systolic function) and intracardiac fibrosis (impairing diastolic and in some cases systolic function).

With severe, long-standing overload, however, the hypertrophied cells begin to deteriorate and die.

Cardiac hypertrophy is a significant risk factor for both mortality and morbidity in the clinical course of heart failure.

However, because of its potent vasodilating properties, nifedipine may be harmful, especially in patients with outflow obstruction.

In many patients, however, the initial benefits decrease with time.

However, all positive inotropic agents except digoxigenin have been found to result in increased long-term mortality, in spite of short-term improvements in cardiac performance.

Another treatment modality is heart transplantation, but this is limited by the availability of donor hearts.

However, despite proven efficacy, response to ACE inhibitors has been limited.

For example, while prolonging survival in the setting of heart failure, ACE inhibitors appear to slow the progression towards end-stage heart failure, and substantial numbers of patients on ACE inhibitors have functional class III heart failure.

Moreover, improvement of functional capacity and exercise time is only small and mortality, although reduced, continues to be high.

Hence, ACE inhibitors consistently appear unable to relieve symptoms in more than 60% of heart failure patients and reduce mortality of heart failure only by approximately 15-20%.

However, when the aorta is constricted in these animals (a model of hypertensive cardiac stress), the hearts still become hypertrophic.

ACE inhibitors would presumably not be able to inhibit these pathways.

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