Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-08-22
2003-12-09
Brumback, Brenda (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S002600, C514S009100, C435S052000, C552S502000, C552S503000, C540S002000
Reexamination Certificate
active
06660725
ABSTRACT:
BACKGROUND OF THE INVENTION
Alzheimer's disease is a common dementing brain disorder of the elderly. The key features of the disease include progressive memory impairment, loss of language and visuospatial skills, and behavior deficits. These changes in cognitive function are the result of degeneration of neurons in the cerebral cortex, hippocampus, basal forebrain, and other regions of the brain. Neuropathological analyses of postmortem Alzheimer's diseased brains consistently reveal the presence of large numbers of neurofibrillary tangles in degenerated neurons and neuritic plaques in the extracellular space and in the walls of the cerebral microvasculature. The neurofibrillary tangles are composed of bundles of paired helical filaments containing hyperphosphorylated tau protein (Lee, V. M and Trojanowski, J. Q, The disordered Cytoskeleton in Alzheimer's disease,
Curr. Opin. Neurobiol
. 2:653 (1992)). The neuritic plaques consist of deposits of proteinaceous material surrounding an amyloid core (Selkoe, D. J., “Normal and abnormal biology of the &bgr;-amyloid precursor protein”,
Annu. Rev. Neurosci
. 17:489-517 (1994)).
Evidence suggests that deposition of amyloid-&bgr; peptide (A&bgr;) plays a significant role in the etiology of Alzheimer's disease. A portion of this evidence is based upon studies which have been generated from data with regard to familial Alzheimer's disease. To date, this aggressive form of Alzheimer's disease has been shown to be caused by missense mutations in (at least) three genes: the amyloid precursor protein (APP) gene itself (Goate, A. et al., “Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease”,
Nature
349:704-706 (1991) and Mullan, M. et al., “A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of &bgr;-amyloid”,
Nature Genet
. 1:345-347 (1992)), and two genes termed presenilins 1 and 2 (Sherrington, R. et al., “Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease”,
Nature
375:754-760 (1995) and Rogaev, E. I. et al., “Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene”,
Nature
376:775-778 (1995)). The missense mutations in APP are located in the region of the protein where proteolytic cleavage normally occurs (see below), and expression of at least some of these mutants results in increased production of A&bgr; (Citron, M. et al., “Mutation of the &bgr;-amyloid precursor protein in familial Alzheimer's disease increases &bgr;-amyloid production”,
Nature
360:672-674 (1992), Cai, X-D. et al., “Release of excess amyloid &bgr; protein from a mutant amyloid &bgr; protein precursor”,
Science
259:514-516 (1993) and Reaume, A. G. et al., “Enhanced amyloidogenic processing of the beta-amyloid precursor protein in gene-targeted mice bearing the Swedish familial Alzheimer's disease mutations and a humanized A&bgr; sequence”,
J Biol. Chem
. 271:23380-23388 (1996)). Initial analyses of the structure of the presenilins did not suggest whether or not they might alter production of A&bgr;, however, recent data has indicated that these mutations cause an increase in A&bgr; secretion (Martins, R. N. et al., “High levels of amyloid-&bgr; protein from S182 (Glu
246
) familial Alzheimer's cells”, 7:217-220 (1995) and Scheuner, D. et al., “Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease”,
Nature Medicine
2:864-870 (1996); Borchelt DR, et al., “Familial Alzheimer's disease-linked presenilin 1 variants elevate A&bgr;1-42/1-40 ratio in vitro and in vivo,”
Neuron
17:1005-1013 (1996); Duff et al., “Increased amyloid-&bgr;42(43) in brains of mice expressing mutant presenilin 1
,” Nature
383:710-713 (1996); Scheuner et al., “Secreted amyloid &bgr;-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease,”
Nature
2:864-870 (1996); Citron et al., “Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid &bgr;-protein in both transfected cells and transgenic mice,”
Nature Medicine
3:67-72 (1997). Tomita et al., “The presenilin 2 mutation (N141) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid &bgr; protein ending at the 42
nd
(or 43
rd
) residue”
Proc Natl Acad Sci USA
94:2025-2030 (1997)). Thus, increased production of A&bgr; is associated with Alzheimer's disease. Corroborating evidence has been derived from at least two other sources. The first is that transgenic mice which express altered APP genes exhibit neuritic plaques and age-dependent memory deficits (Games, D. et al., “Alzheimer-type neuropathology in transgenic mice overexpressing V717F &bgr;-amyloid precursor protein”,
Nature
373:523-525 (1995); Masliah, E. et al., “Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F &bgr;-amyloid precursor protein and Alzheimer's disease”,
J Neurosci
. 16:5795-5811 (1996); Hsiao, K. et al., “Correlative memory deficits, A&bgr; elevation, and amyloid plaques in transgenic mice”,
Science
274:99-103 (1996); Sturchler-Pierrat et al., “Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology,“
Proc Natl Acad Sci USA
94:13287-13292 (1997)). The second piece of evidence comes from study of patients suffering from Down's syndrome, who develop amyloid plaques and other symptoms of Alzheimer's disease at an early age (Mann, D. M. A. and M. M. Esiri, “The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down's syndrome”,
J Neurol. Sci
. 89:169-179 (1989)). Because the APP gene is found on chromosome 21, it has been hypothesized that the increased gene dosage which results from the extra copy of this chromosome accounts for the early appearance of amyloid plaques (Kang, J. et al., “The precursor protein of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor”,
Nature
325:733-736 (1987); Tanzi, R. E. et al., “Amyloid &bgr; protein gene: cDNA, mRNA distribution and genetic linkage near the Alzheimer locus”,
Science
235:880-884 (1987)). Taken together with the evidence derived from cases of familial Alzheimer's disease, the current data suggests that genetic alterations which result in an increase in A&bgr; production can induce Alzheimer's disease.
At present, less is understood about molecular modifications which are associated with the more common, sporadic form of Alzheimer's disease. It is well-established that allelic variation of apolipoprotein E is highly correlated with expression of Alzheimer's disease (Poirier, J., “Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease”,
Trends Neurosci
. 17:525-530 (1994); Roses, A. D. “Perspective on the metabolism of apolipoprotein E and the Alzheimer diseases”,
Exp. Neurol
. 132:149-156 (1995)), but the mechanistic implications of this finding remain elusive. As in familial Alzheimer's disease (Suzuki, N. et al., “An increased percentage of long amyloid &bgr; protein secreted by familial amyloid &bgr; protein precursor (&bgr;APP
717
) mutants”,
Science
264:1336-1340 (1994)) and Down's syndrome (Teller, J. K. et al., “Presence of soluble amyloid &bgr;-peptide precedes amyloid plaque formation in Down's syndrome”,
Nature Medicine
2:93-95 (1996)), A&bgr; deposited in sporadic Alzheimer's disease plaques is typically a longer 42 amino acid version, A&bgr;
42
(Gravina, S. A. et al., “Amyloid beta protein (A beta) in Alzheimer's disease brain: Biochemical and immunocytochemical analysis with antibodies specific for forms ending at A beta 40
Lam Fred Chiu-lai
Reiner Peter B.
Brumback Brenda
Gupta Anish
Seed IP Law Group PLLC
The University of British Columbia
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