Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2002-10-21
2004-11-02
Turner, Sharon (Department: 1647)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C436S503000, C424S130100, C424S178100, C530S300000, C530S402000
Reexamination Certificate
active
06811988
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for diagnosing Alzheimer's disease. In particular, the present invention provides modified beta-amyloid peptides, antibodies that specifically bind to the modified beta-amyloid peptides, and methods of use of these compositions in the diagnosis of Alzheimer's disease, as well as methods to monitor treatment and/or disease progression of Alzheimer's disease in patients. The present invention also provides compositions and methods useful in research involving amyloid precursor protein (APP) metabolism and Alzheimer's disease.
BACKGROUND OF THE INVENTION
Alzheimer's disease (AD) is the fourth most common cause of death in the United States, next to heart disease, cancer and stroke. It 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 suffering from dementia. At present, it is estimated that 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 current public health problems.
To date, Alzheimer's disease is the third most expensive disease in the United States, and costs approximately $100 billion each year. Costs associated with AD include direct medical costs such as nursing home care, direct nonmedical costs such as in-home day care, as well as 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.
Alzheimer's disease 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 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 the causes of and treatments for 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; nor do these models of AD 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]), metal toxicity (Perl et al.,
Science
208:297 [1980]), defects in beta-amyloid protein metabolism (Shijo et al.,
Science
258:126 [1992]; and 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, intensive research has proven that AD is a multifactorial disease with many different, perhaps overlapping, etiologies.
Early detection and identification of Alzheimer's disease facilitate prompt, appropriate treatment and care. However, there is currently no laboratory diagnostic test for Alzheimer's disease. Although studies have suggested that calcium imaging measurement in fibroblasts were of potential clinical use in diagnosing Alzheimer's disease (Peterson et al.,
Neurobiology of Aging
9:261 [1988]; and Peterson et al.,
Proc. Natl. Acad. Sci. USA
83:7999 [1986]), other studies using similar cell lines and techniques have shown no difference in calcium levels in Alzheimer's and normal control fibroblasts (Borden et al.,
Neurobiology of Aging
13:33 [1991]). Thus, there remains a need for diagnostic methods for Alzheimer's disease. In particular, reliable and cost-effective methods and compositions are needed to allow reliable diagnosis of Alzheimer's disease.
SUMMARY OF THE INVENTION
The present invention provides compositions and methods for diagnosing Alzheimer's disease. In particular, the present invention provides modified beta-amyloid peptides, antibodies that specifically bind to the modified beta-amyloid peptides, and methods of use of these compositions for the diagnosis of Alzheimer's disease. The present invention also provides compositions and methods useful in research involving amyloid precursor protein (APP) metabolism and Alzheimer's disease.
The present invention provides isolated and modified &bgr;-amyloid (&bgr;A) peptides comprising at least one malondialdehyde adduct. In one embodiment, the modified &bgr;A peptide comprises the amino acid sequence of SEQ ID NO:1. In another embodiment, the modified &bgr;A peptide comprises at least one malondialdehyde lysine adduct
The present invention also provides purified antibodies directed against a modified &bgr;-amyloid peptide comprising at least one malondialdehyde adduct. In some embodiments, the antibody is a monoclonal antibody, while in other embodiments, the antibody is a polyclonal antibody. In other related embodiments, the invention provides compositions comprising the antibody directed against the modified &bgr;A -peptide comprising at least one malondialdehyde adduct.
The present invention further provides methods for detecting at least one modified &bgr;-amyloid peptide comprising at least one malondialdehyde adduct, comprising the steps of: providing a sample suspected of containing at least one modified &bgr;-amyloid peptide comprising at least one malondialdehyde adduct, and an antibody directed against at least on modified &bgr;-amyloid peptide comprising at least on malondialdehyde adduct; contacting the sample with the antibody under conditions such that the antibody specifically binds to the modified &bgr;-amyloid peptide comprising at least one malondialdehyde adduct, to form an antigen-antibody complex; and detecting the presence of the antigen-antibody complex. In some embodiments, the sample is selected from the group consisting of blood, plasma, serum, serous fluid, and cerebrospinal fluid. In some preferred embodiments, the sample is from a subject. In particularly preferred embodiments, the subject is a human. In further embodiments, the subject is selected from the group consisting of subjects displaying pathology resulting from Alzheimer's disease, subjects suspected of displaying pathology resulting from Alzheimer's disease, and subjects at risk of displaying pathology resulting from Alzheimer's disease. In some particularly preferred embodiments, the methods further comprise the step of diagnosing Alzheimer's disease. In additional particularly preferred embodiments, the Alzheimer's disease diagnosed using the methods of the present invention is selected from the group consisting of late onset Alzheimer's disease, early onset Alzheimer's disease, familial Alzheimer's disease and sporadic Alzheimer's disease. In some preferred embodiments, the methods further comprise the step of monitoring the efficacy of treatment of Alzheimer's disease.
In some preferred embodiments, the methods comprises an enzyme-linked immunosorbent assay. In particularly preferred embodiments, the enzyme-linked immunosorbent assay is selected from the group consist
Buck Martina
Chojkier Mario
Medlen & Carroll LLP
Turner Sharon
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