Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Testing efficacy or toxicity of a compound or composition
Reexamination Certificate
2000-11-28
2004-01-06
Kunz, Gary (Department: 1647)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Testing efficacy or toxicity of a compound or composition
C436S518000, C436S536000
Reexamination Certificate
active
06673332
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides methods and compositions for the treatment of Alzheimer's disease. In particular, the present invention provides methods and compositions suitable to assess inhibitors of neuronal transport of Alzheimer's amyloid precursor protein.
BACKGROUND OF THE INVENTION
Alzheimer's disease (AD) is the fourth most common cause of death in the United States. Presently, Alzheimer's disease is the third most expensive disease in the United States, with costs reaching approximately $100 billion each year for 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. Alzheimer's disease presently afflicts more than four million people, and this number is expected to double during the next forty years with the aging of the population. Alzheimer's disease is also the most common cause of chronic dementia, with approximately two million people in the United States having dementia. At present, it is estimated that approximately ten percent of the population older than 65 years of age have mild to severe dementia. This high prevalence, combined with the rate of growth of the elderly segment of the population, make dementia and particularly Alzheimer's disease, important public health concerns. Medical treatment (including diagnostic and screening methods, as well as treatment regimens) may have economic benefits by slowing the rate of cognitive decline, delaying institutionalization, reducing care giver hours, and improving quality of life.
Alzheimer's disease is a complex multigenic neurodegenerative disorder characterized by progressive impairments in memory, behavior, language, and visuospatial skills, ending ultimately in death. Hallmark pathologies of Alzheimer's disease include granulovascular neuronal degeneration, extracellular neuritic plaques with &bgr;-amyloid deposits, intracellular neurofibrillary tangles and neurofibrillary degeneration, synaptic loss, and extensive neuronal cell death. It is now known that these histopathologic lesions of Alzheimer's disease correlate with the dementia observed in many elderly people.
Research on Alzheimer's disease has led investigators down numerous avenues. Although many models have been proposed, no single model satisfactorily accounts for all neuropathologic findings; nor do these models satisfactorily account for the requirement of aging for disease onset. Cellular changes, leading to neuronal loss and the underlying etiology of the disease, remain unknown. Proposed causes include environmental factors (Perl,
Environmental Health Perspective
63:149 [1985]), such as metal toxicity (Perl et al.,
Science
208:297 [1980]), defects in beta-amyloid protein metabolism (Shijo et al.,
Science
258:126 [1992]; Kosik,
Science
256:780 [1992]), and abnormal calcium homeostasis and/or calcium activated kinases (Mattson et al.,
J. Neuroscience
12:376 [1992]). 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, despite intensive research, much remains to be determined regarding the etiology of Alzheimer's disease. Thus, there remains a need in the art for methods and compositions suitable for treatment of this complex disease.
SUMMARY OF THE INVENTION
The present invention provides methods and compositions for the treatment of Alzheimer's disease. In particular, the present invention provides methods and compositions suitable to assess inhibitors of neuronal transport of Alzheimer's amyloid precursor protein.
The present invention provides methods for identifying modulators of transport of amyloid precursor protein comprising the steps of: providing kinesin-I, amyloid precursor protein, and at least one test compound suspected of having modulating activity; combining kinesin-I, amyloid precursor protein, and the test compound(s) under conditions such that the kinesin-I and amyloid precursor protein will bind to produce a kinesin-I/amyloid precursor protein complex, in the absence of an inhibitor. In preferred embodiments, the binding of the kinesin-I and amyloid precursor protein is detected. In some embodiments, the TPR domain of the light chain of kinesin-I interacts with the amyloid precursor protein. In some preferred embodiments, the binding of the kinesin-I and amyloid precursor protein is inhibited, while in other preferred embodiments, the binding of the kinesin-I and amyloid precursor protein is enhanced. In some embodiments, the binding is detected using any method suitable for the detection of such binding. In some embodiments, the methods used include, but are not limited to co-immunoprecipitation methods, co-immunoprecipitation followed by Western blotting, sucrose gradient centrifugation, microtubule binding assays, column chromatography methods, gel overlays, ATPase assays, and surface plasmon resonance (e.g., BIACORE). In some particularly preferred embodiments, the method comprises a co-immunoprecipitation method. In alternative embodiments, the method further comprises Western blotting. In still further embodiments, the methods involve microtubule binding assays, while in other embodiments, the methods involve ATPase assays, and in additional embodiments, the methods involve sucrose gradient centrifugation. In some preferred embodiments, biochemical methods are used. In alternative preferred embodiments, embodiments, the method is conducted in vivo. In some preferred in vivo methods, the methods are conducted within cells, while in other embodiments, the methods are conducted within an animal (e.g., an animal model of disease). In some embodiments, the methods further comprise the step of exposing an animal to the complex of kinesin-I and amyloid precursor protein. In still further embodiments, the methods are conducted in vitro. The present invention further provides compounds identified using these methods. In some particularly preferred embodiments, the compound(s) identified using the methods of the present invention are provided to an animal to treat neurological illness. In some embodiments, the animal is suffering from a neurological illness. In particularly preferred embodiments, the neurological illness is Alzheimer's disease. In alternative particularly preferred embodiments, the animal is a human.
The present invention also provides methods for identifying compounds that facilitate transport of amyloid precursor protein comprising the steps of: providing an animal capable of producing amyloid precursor protein, wherein the animal has at least one mutation in at least one subunit of kinesin-I, and at least one test compound; administering the test compound(s) to the animal, and detecting the binding of the kinesin-I and amyloid precursor protein. In one embodiment, the test compound inhibits the binding of kinesin-I and amyloid precursor protein, while in an alternative embodiment, the test compound enhances the binding of kinesin-I and amyloid precursor protein. In some embodiments, the kinesin-I encoded by the mutant kinesin-I subunit is functionally normal, while in other embodiments, the kinesin-I encoded by the mutant kinesin-I subunit is mutated. In still further embodiments, the animal having the mutant kinesin-I subunit fails to produce functional kinesin-I. It is not intended that the mutation be limited to any particular mutation, nor is it intended that the mutation particularly affect any specific portion of the kinesin-I molecule. In alternative embodiments, the animal produces abnormal amyloid precursor protein. The present invention further provides compounds identified using these methods.
The present invention also provides methods for treating neurological illness by administering a compound identified using any of the methods described above t
Goldstein Lawrence S. B.
Kamal Adeela
Stokin Gorazd
Kunz Gary
Medlen & Carroll LLP
The Regents of the University of California
Turner Sharon
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