Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1997-03-28
2003-03-18
Scheiner, Laurie (Department: 1648)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C514S04400A, C536S024310, C435S069100, C435S320100, C435S325000
Reexamination Certificate
active
06534641
ABSTRACT:
COMPOSITIONS AND METHODS FOR THE TREATMENT AND DIAGNOSIS OF CARDIOVASCULAR DISEASE
1. INTRODUCTION
2. BACKGROUND OF THE INVENTION
3. SUMMARY OF THE INVENTION
4. DESCRIPTION OF THE FIGURES
5. DETAILED DESCRIPTION OF THE INVENTION
5.1. Identification of Differentially Expressed Genes
5.1.1. Paradigms for the Identification of Differentially Expressed Genes
5.1.1.1. Foam Cell Paradigm
5.1.1.2. Foam Cell Paradigm
5.1.1.3. Foam Cell Paradigm
5.1.1.4. In Vivo Monocyte Paradigm
5.1.1.5. Endothelial Cell—IL-1 Paradigm
5.1.1.6. Endothelial Cell—Shear Stress Paradigm
5.1.2. Analysis of Paradigm Material
5.2. Identification of Pathway Genes
5.3. Characterization of Differentially Expressed and Pathway genes
5.4. Differentially Expressed and Pathway Genes
5.4.1. Differentially Expressed and Pathway Gene Sequences
5.4.2. Differentially Expressed and Pathway Gene Products
5.4.3. Differentially Expressed or Pathway Gene Product Antibodies
5.4.4. Cell—and Animal Based Model Systems
5.4.4.1. Animal Based Systems
5.4.4.2. Cell-Based Assays
5.5. Screening Assays for Compounds that Interact with the Target Gene Product and/or Modulate Target Gene Expression
5.5.1. In Vitro Screening Assays for Compounds that Bind to the Target Gene Product
5.5.2. Assays for Cellular or Extracellular Proteins that Interact with the Target Gene Product
5.5.3. Assays for Compounds that Interfere with Interaction Between Target Gene Product and Other Compounds
5.5.4. Assays for Amelioration of Cardiovascular Disease Symptoms
5.5.5. Monitoring of Effects During Clinical Trials
5.5.6. Assays for Compounds that Modulate Expression of Target Genes
5.6. Compounds and Methods for Treatment of Cardiovascular Disease
5.6.1. Compounds that Inhibit Expression Synthesis or Activity of Mutant Target Gene Activity
5.6.1.1. Inhibitory Antisense, Ribozyme, Triple Helix, and Gene Inactivation Approaches
5.6.1.2. Antibodies for Target Gene Products
5.6.2. Methods for Restoring or Enhancing Target Gene Activity
5.7. Pharmaceutical Preperations and Methods of Administration
5.7.1. Effective Dose
5.7.2. Formulations and Use
5.8. Diagnosis of Cardiovascular Disease Abnormalities
5.8.1. Detection of Fingerprint Gene Nucleic Acids
5.8.2. Detection of Fingerprint Gene Peptides 5.8.3. Imaging Cardiovascular Disease Conditions
6. Example: IDENTIFICATION OF GENES DIFFERENTIALLY EXPRESSED IN RESPONSE TO PARADIGM A: IN VITRO FOAM CELL PARADIGM
6.1. Materials and Methods
6.1.1. Cell Isolation and Culturing
6.1.2. Analysis of Paradigm Material
6.1.3. Chromosomal Localization of Target Genes
6.2. Results 7. EXAMPLE: IDENTIFICATION OF GENES DIFFERENTIALLY EXPRESSED IN RESPONSE TO PARADIGM D: ENDOTHELIAL CELL SHEAR STRESS
7.1. Materials and Methods
7.2. Results
8. EXAMPLE: USE OF GENES UNDER PARADIGM A AS SURROGATE MARKERS IN CLINICAL TRIALS
8.1. Treatment of Patients and Cell Isolation
8.2. Analysis of Samples
9. EXAMPLE: IMAGING OF A CARDIOVASCULAR DISEASE CONDITION
9.1. Monoclonal Conjugated Antibodies
9.2. Administration and Detection of Imaging Agents
10. POLYCLONAL ANTIBODIES TO TARGET GENE PEPTIDE SEQUENCES
11. EXAMPLE: THE RCHD534 AND FCHD540 GENE PRODUCTS INTERACT
11.1. Materials and Methods
11.1.1. Yeast, Strains, Media, and Microbiological Techniques
11.1.2. Plasmid and Yeast and Strain Construction
11.1.3. Two-Hybrid Screening
11.1.4. Paper Filter Beta-Galactosidase Assays
11.2 Results
11.2.1. Strong Physical Interaction of RCHD534 and FCHD540 Measured by Two-Hybrid Assay—128
11.2.2. Identification of Proteins that Physically Interact with FCHD540
11.2.3. Retransformation and Specificity Testing of TCHV03A and TCHVR4A
11.3. Further analysis of RCHD534 and FCHD540 Function
11.3.1. Tissue Expression Patterns
11.3.2. Cellular Localization
11.3.3. Protein Interactions in human Cells
11.3.4. Effect of Expression on TGF-B Signaling
12. EXAMPLE: ANTISENSE AND RIBOZYME MOLECULES FOR INHIBITION OF RCHD534 AND FCHD540 EXPRESSION
13. DEPOSIT OF MICROORGANISMS
1. INTRODUCTION
The present invention relates to methods and compositions for the treatment and diagnosis of cardiovascular disease, including, but not limited to, atherosclerosis, ischemia/reperfusion, hypertension, restenosis, and arterial inflammation. Genes which are differentially expressed in cardiovascular disease states, relative to their expression in normal, or non-cardiovascular disease states are identified. Genes are also identified via the ability of their gene products to interact with other gene products involved in cardiovascular disease. The genes identified may be used diagnostically or as targets for therapeutic intervention. In this regard, the present invention provides methods for the identification and therapeutic use of compounds in the treatment and diagnosis of cardiovascular disease. Additionally, methods are provided for the diagnostic monitoring of patients undergoing clinical evaluation for the treatment of cardiovascular disease, for monitoring the efficacy of compounds in clinical trials, and for identifying subjects who may be predisposed to cardiovascular disease.
2. BACKGROUND OF THE INVENTION
Cardiovascular disease is a major health risk throughout the industrialized world. Atherosclerosis, the most prevalent of cardiovascular diseases, is the principal cause of heart attack, stroke, and gangrene of the extremities, and thereby the principal cause of death in the United States. Atherosclerosis is a complex disease involving many cell types and molecular factors (for a detailed review, see Ross, 1993, Nature 362: 801-809). The process, in normal circumstances a protective response to insults to the endothelium and smooth muscle cells (SMCs) of the wall of the artery, consists of the formation of fibrofatty and fibrous lesions or plaques, preceded and accompanied by inflammation. The advanced lesions of atherosclerosis may occlude the artery concerned, and result from an excessive inflammatory-fibroproliferative response to numerous different forms of insult. For example, shear stresses are thought to be responsible for the frequent occurrence of atherosclerotic plaques in regions of the circulatory system where turbulent blood flow occurs, such as branch points and irregular structures.
The first observable event in the formation of an atherosclerotic plaque occurs when blood-borne monocytes adhere to the vascular endothelial layer and transmigrate through to the sub-endothelial space. Adjacent endothelial cells at the same time produce oxidized low density lipoprotein (LDL). These oxidized LDL's are then taken up in large amounts by the monocytes through scavenger receptors expressed on their surfaces. In contrast to the regulated pathway by which native LDL (nLDL) is taken up by nLDL specific receptors, the scavenger pathway of uptake is not regulated by the monocytes.
These lipid-filled monocytes are called foam cells, and are the major constituent of the fatty streak. Interactions between foam cells and the endothelial and SMCs which surround them lead to a state of chronic local inflammation which can eventually lead to smooth muscle cell proliferation and migration, and the formation of a fibrous plaque. Such plaques occlude the blood vessel concerned and thus restrict the flow of blood, resulting in ischemia.
Ischemia is a condition characterized by a lack of oxygen supply in tissues of organs due to inadequate perfusion. Such inadequate perfusion can have number of natural causes, including atherosclerotic or restenotic lesions, anemia, or stroke, to name a few. Many medical interventions, such as the interruption of the flow of blood during bypass surgery, for example, also lead to ischemia. In addition to sometimes being caused by diseased cardiovascular tissue, ischemia may sometimes affect cardiovascular tissue, such as in ischemic heart disease. Ischemia may occur in any organ, however, that is suffering a lack of oxygen supply.
The most common cause of ischemia in the heart is atherosclerotic disease of epicardial coronary arteries. By reducing the lumen of these vessels, atherosclerosis causes an absolute decrease in myocardial perfusion
Falb Dean A.
Gimbrone, Jr. Michael A.
Millennium Pharmaceuticals Inc.
Pennie & Edmonds LLP
Scheiner Laurie
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