Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-11-27
2001-02-20
Criares, Theodore J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C365S042000, C365S042000
Reexamination Certificate
active
06191154
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods and compositions for treating Alzheimer's disease and other diseases and conditions with an inflammatory component (e.g., central nervous system injury). In particular, the present invention provides agents that regulate the production of proinflammatory and neurotoxic products involved in Alzheimer's disease and other inflammatory diseases.
BACKGROUND OF THE INVENTION
Alzheimer's disease (AD) is a complex multi-genic neurodegenerative disorder characterized by progressive impairments in memory, behavior, language, and visuo-spatial skills, ending ultimately in death. Hallmark pathologies within vulnerable regions include extracellular &bgr;-amyloid deposits, intracellular neurofibrillary tangles, synaptic loss, and extensive neuronal cell death. Research on the causes and treatments of Alzheimer's disease has led investigators down numerous avenues. Although many models have been proposed, no single model of AD satisfactorily accounts for all neuropathologic findings as well as the requirement of aging for disease onset. The mechanisms of disease progression are equally unclear. Considerable human genetic evidence has implicated alterations in production or processing of the human amyloid precursor protein (APP) in the etiology of the disease. However, intensive research has proven that AD is a multifactorial disease with many different, perhaps overlapping, etiologies.
To date, Alzheimer's disease is the third most expensive disease in the United States, costing society approximately $100 billion each year. It is one of the most prevalent illnesses in the elderly population, and with the aging of society, will become even more significant. Costs associated with AD include direct medical costs such as nursing home care, direct nonmedical costs such as in-home day care, and indirect costs such as lost patient and care giver productivity. Medical treatment may have economic benefits by slowing the rate of cognitive decline, delaying institutionalization, reducing care giver hours, and improving quality of life. Pharmacoeconomic evaluations have shown positive results regarding the effect of drug therapy on nursing home placement, cognition, and care giver time.
Thus far, the therapeutic strategies attempted have targeted neurotransmitter replacement, or the preservation of normal brain structures, which potentially provide short-time relief, but do not prevent neuronal degeneration and death. Thus, there is a need for therapies that prevent neuronal degeneration and death associated with Alzheimer's disease and provide long-term relief.
SUMMARY OF THE INVENTION
The present invention relates to methods and compositions for treating Alzheimer's disease and other diseases and conditions with an inflammatory component (e.g., central nervous system injury). In particular, the present invention provides agents that regulate the production of proinflammatory and neurotoxic products involved in Alzheimer's disease and other inflammatory diseases.
The present invention provides methods for treating a subject, comprising administering a therapeutically effective amount of a PPAR&ggr; agonist to the subject, wherein the subject is selected from the group consisting of subjects suffering from Alzheimer's disease and subjects susceptible to Alzheimer's disease.
The present invention also provides methods for treating a subject suffering from central nervous system injury, comprising administering a therapeutically effective amount of a PPAR&ggr; agonist to the subject suffering from central nervous system injury.
The present invention further provides methods for treating a subject, comprising administering a therapeutically effective amount of a PPAR&ggr; agonist to the subject, wherein the subject is selected from the group consisting of subjects suffering from a disease with an inflammatory component and subjects susceptible to a disease with an inflammatory component. In some embodiments, the disease with an inflammatory component is selected from the group consisting of Alzheimer's disease, stroke, traumatic injury, and spinal injury, although it is contemplated that the methods of the present invention find use in the treatment of any disease with an inflammatory component.
In some embodiments of the present invention, the PPAR&ggr; agonist comprises a thiazolidinedione, although all PPAR&ggr; ligands and regulatory factors are contemplated by the present invention. In some embodiments, the thiazolidinedione comprises, but is not limited to, troglitazone, ciglitazone, pioglitazone, BRL 49653, englitazone, or combinations thereof. In other embodiments, the PPAR&ggr; agonist comprises, but is not limited to, docosahexaenoic acid, prostaglandin J
2
and prostaglandin J
2
analogs (e.g.,
12
-prostaglandin J
2
and 15-deoxy-&Dgr;
12,14
-prostaglandin J
2
).
In some embodiments of the present invention, the administering comprises oral administering, although all administration means are contemplated. In some embodiments, the therapeutically effective amount of the PPAR&ggr; agonist comprises approximately 10 mg/kg per day, although greater or lessor amounts are contemplated by the present invention.
The present invention also provides methods for measuring the ability of a compound (e.g., agonists and antagonists) to modify PPAR&ggr;-mediated gene transcription of the cox-2 gene, comprising: providing one or more test compounds; and a host cell transfected with a DNA construct comprising an oligonucleotide sequence comprising, in operable order, 1) a PPAR&ggr;-sensitive cox-2 regulatory element 2) a promoter and 3) a heterologous gene; and contacting the one or more test compounds with the host cell under conditions in which expression of the heterologous gene is responsive to the one or more compounds. In some embodiments, the method further comprises the step of comparing the level of gene expression of the heterologous gene in step b) with the level of gene expression from the host cell in the absence of the one or more compounds. In one preferred embodiment of the present invention, the DNA construct comprising an oligonucleotide sequence comprising a PPAR&ggr;-sensitive cox-2 regulatory element comprises SEQ ID NO:1.
The present invention further provides a method for regulating COX-2 expression, comprising: providing one or more cells expressing COX-2; means for expressing PPAR&ggr; in the one or more cells; and one or more PPAR&ggr; agonists; and introducing into the one or more cells, in any order, the means for expressing PPAR&ggr; and the one or more PPAR&ggr; agonists. In some embodiment, the one or more cells expressing COX-2 comprise cell that express an abnormal level of COX-2.
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Combs Colin
Fitch Michael T.
Landreth Gary
Silver Jerry
Case Western Reserve University
Criares Theodore J.
Medlen & Carroll LLP
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