Chemistry: molecular biology and microbiology – Apparatus
Reexamination Certificate
1999-12-15
2004-03-23
Lacourciere, Karen A. (Department: 1635)
Chemistry: molecular biology and microbiology
Apparatus
C435S287200, C435S006120, C536S024300, C536S024330, C536S024310, C536S023100
Reexamination Certificate
active
06709855
ABSTRACT:
I. INTRODUCTION
The present invention relates to methods and compositions for the detection, diagnosis, prevention and treatment of disease states and related disorders. The disease states of the present invention include cardiac, kidney and inflammatory disease. Specifically, genes that are differentially expressed in the cells, tissues, or peripheral blood of a subject suffering from, or predisposed to, such disease states may be identified through the methods of the present invention.
The present invention also relates to compositions and methods useful in the diagnosis, prevention and therapeutic treatment of disease states through the use of the differentially expressed genes of the present invention. Methods and compositions are provided for the diagnostic evaluation and prognosis of conditions involving such disease states, for the identification of subjects exhibiting a predisposition to such conditions, for therapeutic uses, e.g., modulating the effect of such differentially expressed genes, for monitoring subjects undergoing clinical evaluation for the prevention and treatment of a disease and its disorders, and for monitoring the efficacy of compounds used in clinical trials.
II. BACKGROUND OF THE INVENTION
The present invention relates generally to methods and compositions for the detection, diagnosis, prevention and treatment of a disease, specifically cardiac, kidney or inflammatory disease, and related disorders. Particularly, the present invention relates to methods useful in diagnosing, identifying, monitoring, preventing, and treating the onset and progression of such disease states through the use of genes and gene products differentially expressed in a disease, specifically cardiac, kidney or inflammatory disease, along with modulators thereof.
By way of example, congestive heart failure (CHF) is a major cardiac disease associated with extensive morbidity and mortality. Traditionally, CHF has been treated by a series of agents including diuretics, vasodilators, angiotensin converting enzyme inhibitors, &bgr;-adrenergic antagonists, and positive inotropes like digoxin. These drugs, however, principally provide symptomatic relief and typically only extend the life of one suffering from the disease for periods ranging from 6-12 months.
In response to hormonal, physiological, hemodynamic and pathological stimuli, adult ventricular muscle cells can adapt to increased workloads through the activation of a hypertrophic process. This process is characterized by an increase in the contractile protein content of cardiac muscle cells without a proliferative response because the adult cardiomyocyte is terminally differentiated and has lost its ability to divide. Cardiac growth during the hypertrophic process therefore results primarily from an increase in protein content per individual cardiomyocyte, with little or no change in cell number. The acquisition of the cardiac hypertrophic phenotype is in part dependent upon the activation of cardiac muscle gene program.
In addition to the induction of specific contractile protein components ventricular hypertrophy is also characterized by alterations in the expression of certain non-contractile proteins, such as atrial natriuretic peptide (ANP, also known as ANF). During embryonic development, the ANP gene is expressed in both the atrium and the ventricle. However, shortly after birth ANP expression is down regulated in the ventricle and expression is mainly confined to the atrium. Following induction of hypertrophy, ANP is reexpressed in the ventriculum. Thus, ANP expression can be considered to be a non-contractile protein marker of cardiac ventricular hypertrophy.
Ventricular hypertrophy is initially a compensatory mechanism by which the heart is attempting to counteract the effects of conditions like pressure overload, loss of contractile tissue, obstruction of blood flow, or increased peripheral demand for blood flow, all of which can be generated by a variety of physiological or pathological stimuli. In some circumstances, such as, injury or functional compromise of the heart, a typically short term, compensated hypertrophic response is desirable. Similarly, cardiac, e.g. left ventricular, hypertrophy (physiological hypertrophy) is often observed in some highly trained athletes, without any apparent cardiovascular complications. However, under some circumstances the hypertrophic response may eventually contribute to cardiac dysfunction. These circumstances include, but are not limited to, excessive hypertrophy, prolonged hypertrophy, or hypertrophy occurring in the context of toxic factors or toxic concentrations of factors that, when combined with the hypertrophic response of cardiac myocytes, result in mechanical dysfunction, electrical conduction dysfunction, loss of cardiac wall elasticity, or stimulation of fibrosis. In these cases hypertrophy is termed decompensated hypertrophy, and antagonism of cardiac hypertrophy is considered desirable. Once the transition from compensated to decompensated hypertrophy is achieved, the progression to a terminal heart failure phenotype often rapidly follows.
Heart failure affects approximately five million Americans. New cases of heart failure number about 400,000 each year. The pathophysiology of CHF is rather complex. Generally, the central hallmark of the disease is the inability of the heart to pump sufficient oxygenated blood to meet the demands of peripheral tissues. Numerous etiologies contribute to the development of CHF, including primary diseases of, or insults to, the myocardium itself, cardiac defects, hypertension, inflammation, kidney disease and vascular disease. These conditions lead to the hypertrophy and remodeling of the cardiac ventricles which, if unchecked, ultimately reduce the mechanical performance of the heart. Forces associated with the inability of the heart to pump blood ultimately lead to the release of neurohormones like catecholamines, renin-angiotensin, aldosterone, endothelin and related factors into the circulation. It has been demonstrated that elevations in plasma levels of many of these circulating neurohormones have a deleterious impact on the outcome of patients with CHF. Local production of these neurohormonal factors in the heart is believed to contribute centrally to the disease. Thus, an important therapeutic strategy has been to block this neurohormonal axis contributing to the pathogenesis of this disease.
Factors known to contribute centrally to the pathophysiology of heart disease are biosynthesized in the heart itself. These factors are produced in cardiac myocytes, fibroblasts, smooth muscle and endothelial cells, and inflammatory cells associated with the myocardium. For example, the heart has been shown to contain its own renin-angiotensin system. Blockade of the cardiac renin-angiotensin system is believed to contribute significantly to the therapeutic efficacy of the therapeutic class of agents known as angiotensin converting enzyme (ACE) inhibitors.
The heart also produces other factors including, but not limited to, endothelins, bradykinin, adrenomedullin, tumor necrosis factor, transforming growth factors, and natriuretic peptides. Unfortunately, therapeutic strategies are limited to the modulation of such substances, which are already known to contribute to the disease. Indeed, it is estimated that the functional contributions of only a minor fraction of all known secreted factors encoded by the human genome have been defined. Thus, it would be beneficial to discover differentially expressed genes related to disease states, in addition to methods and compositions for the diagnostic evaluation and prognosis of conditions involving such diseases, for the identification of subjects exhibiting a predisposition to such conditions, for modulating the effect of these differentially expressed genes and their expression products, for monitoring patients undergoing clinical evaluation for the prevention and treatment of a disease, specifically cardiac, kidney or inflammatory disease, and its disorders, and for monitoring the eff
Damm Deborah L.
Joly Alison
Lewicki John A.
Schreiner George F.
Stanton Lawrence W.
Lacourciere Karen A.
Morrison & Foerster / LLP
Scios Inc.
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