Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-12-14
2001-08-21
Low, Christopher S. F. (Department: 1653)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023100, C536S023500, C424S093200, C424S093100, C424S093210, C435S069100, C435S325000, C435S352000, C435S320100, C530S300000, C530S350000
Reexamination Certificate
active
06277974
ABSTRACT:
TABLE OF CONTENTS
1 INTRODUCTION
2 BACKGROUND OF THE INVENTION
2.1 Mechanisms which Lead to Cell Death
2.2 Selected Factors and Conditions which Inhibit Cell Death Mechanisms
3 SUMMARY OF THE INVENTION
3.1 Definitions
4 BRIEF DESCRIPTION OF THE FIGURES
5 DETAILED DESCRIPTION OF THE INVENTION
5.1 The Protective Sequences
5.2 Protein Products of the Protective Sequences
5.3 Antibodies to the Protective Sequence Products
5.4 Uses of the Protective Sequences, Protective Sequence Products and Antibodies
5.4.1 Composition and Methods for the Treatment of Conditions, Disorders, or Diseases Involving Cell Death
5.4.1.1 Examples of Conditions, Disorders, or Diseases Involving Cell Death
5.4.1.2 Modulatory Antisense, Ribozyme and Triple Helix Approaches
5.4.1.3 Gene Replacement Therapy
5.4.1.4 Detection of Protective Nucleic Acid Molecules
5.4.1.5 Detection of Protective Sequence Products
5.4.2 Screening Assays for Compounds which Interact with Protective Sequence Products or Modulate Protective Sequence Activity
5.4.2.1 In Vitro Screening Assays for Compounds which Bind to Protective Sequence Products
5.4.2.2 Assays for Proteins which Interact with Protective Sequence Products
5.4.2.3 Assays for Compounds which Interfere with or Potentiate Protective Sequence Products Macromolecule Interaction
5.4.2.4 Assays for the Identification of Compounds which Modulate Conditions, Disorders, or Diseases Involving Cell Death
5.4.3 Additional Uses for the Protective Sequences, Protective Sequence Products, or Their Regulatory Elements
5.5 Pharmaceutical Preparations and Methods of Administration
5.5.1 Effective Dose
5.5.2 Formulations and Use
6 EXAMPLE: SEQUENCE AND CHARACTERIZATION OF PROTECTIVE SEQUENCES
6.1 Materials and Methods
6.1.1 Preparation of DNA
6.1.2 Sequence Characterization of the DNA
6.1.3 Sequence Comparison
6.1.4 Immuno-Cytochemistry Protocol for the Characterization of Protected Cells
6.2 Results
6.2.1 Protective sequence CNI-0071
6.2.2 Protective sequence CNI-00712
6.2.3 Protective sequence CNI-00714
6.2.4 Protective sequence CNI-00715
6.2.5 Protective sequence CNI-00716
6.2.6 Protective sequence CNI-00717
6.2.7 Protective sequence CNI-00720
6.2.8 Protective sequence CNI-00721
6.2.9 Protective sequence CNI-00723
6.2.10 Protective sequence CNI-00724
7 DEPOSIT OF MICROORGANISMS
8 REFERENCES CITED
1 INTRODUCTION
The present invention relates to compositions and methods for the treatment and diagnosis of conditions, disorders, or diseases involving cell death, including, but not limited to, neurological disorders such as stroke. Nucleic acids are described herein which, when introduced into a cell either predisposed to undergo cell death or in the process of undergoing cell death, prevent, delay, or rescue the cell from death relative to a corresponding cell into which no exogenous nucleic acids have been introduced Such nucleic acids are referred to as “protective sequences”. Protective sequences or their products are identified by their ability to prevent, delay, or rescue a cell, cells, tissues, organs, or organisms from dying. Protective sequences or their products are also identified via their ability to interact with other genes or gene products involved in conditions or disorders involving cell death.
The invention further includes recombinant DNA molecules and cloning vectors comprising protective sequences, and host cells and host organisms engineered to contain such DNA molecules and cloning vectors. The present invention further relates to protective sequence products and to antibodies directed against such protective sequence products.
The protective sequences identified, their products, or antibodies may be used diagnostically, prophylactically, therapeutically or as targets for therapeutic intervention. In this regard, the present invention provides methods for the identification and prophylactic or therapeutic use of compounds in the treatment and diagnosis of conditions, disorders, or diseases involving cell death. Additionally, methods are provided for the diagnostic monitoring of patients undergoing clinical evaluation for the treatment of conditions or disorders involving cell death, for monitoring the efficacy of compounds in clinical trials and for identifying subjects who may be predisposed to such conditions, disorders, or diseases involving cell death.
2 BACKGROUND OF THE INVENTION
2.1 Mechanisms which Lead to Cell Death
It is widely recognized that at least two distinct cell death mechanisms exist for mammalian cells. These two mechanisms are necrosis and apoptosis, and are significant components of numerous conditions, disorders and disease states.
Necrosis plays an important physiologic role in signaling the presence of certain conditions. When cells die as a result of necrosis, the dying cells release substances that activate the body's immune response in a local, and in some cases widespread, reaction to the necrosis-inducing condition. This response is important in, for example, bacterial infection.
Experimental evidence in a wide variety of cells throughout the body has revealed that every cell can initiate a program of self-destruction, called apoptosis. This program can be initiated by a wide variety of natural and unnatural events. There are at least four distinct pathways for executing this program of cell death, and it is virtually certain that dozens, if not hundreds, of different intracellular biochemical cascades interact with each pathway. It is equally likely that certain cell types, such as cells in the heart or neurons, will utilize specialized signaling pathways that are not generally represented elsewhere in the body. However, since cell death is neither always necessary nor desired, it would be desirable to manipulate the manner in which cells start their death process. In some circumstances, preventing, delaying, or rescuing cells from death would either alleviate the disease or allow more time for definitive treatment to be administered to the patient. An example of this situation is brain cell death caused by ischemic stroke: preventing, delaying, or rescuing cells from death until the blood supply to the brain could be restored would greatly reduce, if not eliminate, the possibility of a person's death and/or long-term disability from stroke (Lee J M, et al.
Nature
1999, 399(supp): A7-A14; Tarkowski E, et al.
Stroke
1999, 30(2): 321-7; Pulera M R, et al.
Stroke
1998, 29(12): 2622-30). In still other circumstances, the failure of cells to die may itself lead to disease such as cancer (Hetts S W.
JAMA
1998, 297(4): 300-7).
Cell death plays an important role in the normal function of mammalian organisms. While it may seem counterintuitive for cells to have death as a normal part of their life cycle, controlled and physiologically appropriate cell death is important in regulating both the absolute and relative numbers of cells of a specific type. (Hetts S W.
JAMA
1998, 297(4): 300-7; Garcia I, et al.
Science
1992, 258(5080): 302-4). When the mechanism of apoptosis does not function properly and normal cell death does not occur, the resulting disease is characterized by unregulated cellular proliferation, as occurs in a neoplastic disease or an autoimmune disease (Hetts S W.
JAMA
1998, 297(4): 300-7; Yachida M, et al.
Clin Exp Immunol
1999, 116(1): 140-5).
One method for regulating cell death involves manipulating the threshold at which the process of cell death begins. This threshold varies significantly by cell type, tissue type, the type of injury or insult suffered by the cell, cellular maturity, and the physiologic conditions in the cell's environment (Steller H.,
Science
1995, 267(5203): 1445-9). Although it is probable that certain cellular injuries or insults irrevocably induce death, lesser injuries or insults may begin the dying process without inducing irreversible cell death. What constitutes a lesser injury or insult may vary tremendously with changes in the factors influencing that cell's death threshold. The ability to alter a cell's threshold for responding to an injury or insult,
Barney Shawn
Katz Lawrence C.
Lo Donald C.
Portbury Stuart D.
Puranam Kasturi
Cogent Neuroscience, Inc.
Low Christopher S. F.
Robinson Patricia
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