Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of...
Reexamination Certificate
1999-08-16
2002-10-22
Nguyen, Daue Trong (Department: 1632)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
C435S069100, C435S320100, C536S023100, C536S024310, C536S023500
Reexamination Certificate
active
06468791
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to Alzheimer's disease, and more specifically to methods and compositions for use in diagnosis and treatment of Alzheimer's Disease.
BACKGROUND OF THE INVENTION
Alzheimer's disease (AD) is a devastating, neurodegenerative progressive disorder first recognized in 1907 (Alzheimer,
Algemeine Zeitschrift fur Psychiatrie
64:146-148, 1907). AD is a common disease in the elderly and is the predominant cause of dementia in people over 65 years of age. The prevalence of AD is estimated to be as high as 18.7% and 47.2% for the 75-84 year and ≧85 year age groups respectively. Thus, there is a large affected population in most countries of the world.
Clinical symptoms of the disease typically begin with subtle short term memory problems. As the disease progresses, difficulty with memory, language, and orientation worsen to the point of interfering with the ability of the person to function independently. Other symptoms, which are variable, include myoclonus and seizures. Duration of AD from the first symptoms of memory loss until death is 10 years on average, but may range from 6-8 years to more than 20 years. AD always results in death, often from respiratory-related illness.
The pathology in AD is confined exclusively to the central nervous system (CNS). The predominant features are amyloid deposits (plaques) and neurofibrillary tangles (NFT). In AD, amyloid is found associated with the vascular system of the CNS and as focal deposits in the parenchyma. The major molecular component of amyloid is a highly hydrophobic peptide called the A&bgr; peptide. This peptide aggregates into filaments in an anti-&bgr;-pleated sheet structure resulting in the birefringent nature of the AD amyloid. While A&bgr; is the major component of AD amyloid, a partial list of other proteins associated with the amyloid includes &agr;-1-anti-chymotrypsin (Abraham, et al.,
Cell
52:487-501, 1988), cathepsin D (Cataldo, et al.,
Brain Res
. 513:181-192, 1990), non-amyloid component protein (Ueda, et al.,
Proc. Natl Acad. Sci. USA
90:11282-11286, 1993), apolipoprotein E (apoE) (Namba, et al.,
Brain Res
. 541:163-166, 1991; Wisniewski and Frangione,
Neurosci. Lett
. 135:235-238, 1992; Strittmatter, et al.,
Proc. Nat. Acad. Sci. USA
90:1977-1981, 1993), apolioprotein J (Choi-Mura, et al.,
Acta Neuropathol
. 83:260-264, 1992; McGeer, et al.,
Brain Res
. 579:337-341, 1992), heat shock protein 70 (Hamos, et al.,
Neurology
41:345-350, 1991), complement components (McGeer and Rogers,
Neurology
43:447-449, 1992), &agr;
2
-macroglobin (Strauss, et al.,
Lab. Invest
. 66:223-230, 1992), interleukin-6 (Strauss, et al.,
Lab. Invest
. 66:223-230, 1992), proteoglycans (Snow, et al.,
Lab. Invest
. 58:454-458, 1987), and serum amyloid P (Coria, et al.,
Lab. Invest
. 58:454-458, 1988). Surrounding many plaques are dystrophic neurites, which are nerve endings containing abnormal filamentous structures. Plaques are often surrounded by astrocytes and activated microglial cells expressing immune-related proteins, such as the MHC class II glycoproteins HLA-DR, HLA-DP, and HLA-DQ as well as MHC class I glycoproteins, interleukin-2 (IL-2) receptors, and IL- 1. The other dominant feature of AD neuropathology is the presence of NFTs. These consist of abnormal filaments bundled together in neuronal cell bodies. “Ghost” NFTs are also observed in AD brains, which presumably mark the location of dead neurons. Other neuropathological features include granulovacuolar changes, neuronal loss, gliosis and the variable presence of Lewy bodies.
In the AD brain, the destructive process of the disease is evident on a gross level. In the late-stage of AD, ventricular enlargement and shrinkage of the brain can be observed by magnetic resonance imaging. On autopsy, extensive gliosis and neuronal loss are observed. Thus, the amyloid plaque structures and NFTs observed at autopsy are most likely the end-points of a lengthy disease process, far removed from the initiating events of AD. Also, the cells remaining at autopsy are grossly different from those of a normal brain. Neurons, which were possibly involved in initiating events, are absent and other cell types, such as the activated microglial cells and astroctyes, have gene expression patterns not observed in the normal brain. Thus, attempts using biochemical methods to identify key proteins and genes in the initiating steps of the disease are hampered by the fact that it is not possible to actually observe these critical initiating events. Rather, biochemical dissection of the AD brain at autopsy is akin to molecular archeology, attempting to reconstruct the pathogenic pathway by comparing the normal brain to the end-stage disease brain.
Substantial evidence has suggested that inherited genetic defects are involved in AD. Numerous early-onset kindreds have been described (Bird, et al.,
Ann. Neurol
. 23:25-31, 1988; Bird, et al.,
Ann. Neurol
. 25:12-25, 1989; Cook, et al.,
Neurology
29:1402-1412, 1979; Feldman, et al.,
Neurology
13:811-824, 1960; Goudsmit,
J. Neuro.l Sci
. 49:79-, 1981; Heston and White,
Behavior Genet
. 8:315-331, 1978; Martin, et al.,
Neurology
41:62-68, 1991; Nee, et al.,
Arch. Neurol
. 40:203-208, 1983; van Bogaeert, et al.,
Mschr. Psychait. Neurol
. 102:249-301, 1940; Wheelan,
Ann. Hum. Genet
. 23:300-309, 1959). (Early-onset is defined herein as onset prior to 65 years.) Families with multiple late-onset AD cases have also been described (Bird, et al.,
Ann. Neurol
. 25:12-25, 1989; Heston and White,
Behavior Genet
. 8:315-331, 1978; Pericak-Vance, et al.,
Exp. Neurol
. 102:271-279, 1988). In addition, twin studies have documented that monozygotic twins are more concordant in their AD phenotype than dizygotic twins (Nee, et al.,
Neurology
37:359-363, 1987; [133]). Also, the families of concordant twins have more secondary cases of AD than families of discordant twins (Rapoport, et al.,
Neurology
41:1549-1553, 1991).
Genetic dissection of AD has been complicated by the complexity of the disease and the limited accuracy of its diagnosis. Because AD is common in the elderly, clustering of cases in a family may occur by chance, representing possible confounding non-allelic genetic heterogeneity, or etiologic heterogeneity with genetic and non-genetic cases co-existing in the same kindred. In addition, the clinical diagnosis of AD is confounded with other dementing diseases common in the elderly.
Despite the problems associated with resolving complex genetic diseases, 2 causative AD loci and 1 risk-modifying gene have been identified. Mutations in the amyloid precursor protein (APP) gene on chromosome 21 cause early-onset (<65 years) autosomal dominant AD (Goate, et al.,
Nature
349:704, 1991). Mutations in a recently identified gene (AD3) on chromosome 14 also result in early-onset autosomal dominant AD (Schellenberg, et al.,
Science
258:668, 1992; Sherrington, et al.,
Nature
375:754-760, 1995). For late-onset AD, the APOE gene has been identified as a genetic modifying factor (Strittmatter, et al.,
Proc. Natl. Acad. Sci. USA
90:1977, 1993; Corder, et al.,
Science
261:921, 1993; Corder, et al.,
Nat. Genet
. 7:180-184, 1994; Benjamin, et al.,
Lancet
344:473, 1994; Smith, et al.,
Lancet
344:473-474, 1994).
The known genetic loci for AD do not account for all cases of AD. For example, in late-onset AD approximately half of AD cases do not have the APOE &egr;4 allele (Brousseau, et al.,
Neurology
342, 1994; Kuusisto, et al.,
Brit. Med J
. 309:636, 1994; Tsai, et al.,
Am. J. Hum. Genet
. 54: 643, 1994; Liddel, et al.,
J Med. Genet
. 31:197, 1994). Also, in the Volga German (VG) kindreds (Cook, et al.,
Neurology
29:1402, 1979; Bird, et al.,
Ann. Neurol
. 23:25, 1988; Bird, et al.,
Ann. Neurol
. 25:12, 1989; Bird,
Am. Hist. Soc. Germ. Russia J
. 49:1991; Bird, et al., in
Heterogeneity of Alzheimer's Disease
, F. Boller, et al., Eds. (Spring-Verlag, Heidelberg, 1992) pp. 118-129), as in several other families with high incidence of AD, the k
Bird Thomas D.
Galas David J.
Levy-Lahad Ephrat
Schellenberg Gerard D.
Tanzi Rudolph E.
Nguyen Daue Trong
Seed IP Law Group
The General Hospital Corp.
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