Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-05-05
2004-01-27
Ponnaluri, Padmashri (Department: 1627)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S007100, C435S091500, C435S091500, C435S091500, C435S091500, C530S333000
Reexamination Certificate
active
06682888
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a composition comprising a plurality of cDNAs which are differentially expressed in Alzheimer's disease and which may be used entirely or in part to diagnose, to stage, to treat, or to monitor the treatment of a subject with a brain disorder.
BACKGROUND OF THE INVENTION
Array technology can provide a simple way to explore the expression of a single polymorphic gene or the expression profile of a large number of related or unrelated genes. When the expression of a single gene is examined, arrays are employed to detect the expression of a specific gene or its variants. When an expression profile is examined, arrays provide a platform for examining which genes are tissue specific, carrying out housekeeping functions, parts of a signaling cascade, or specifically related to a particular genetic predisposition, condition, disease, or disorder.
The potential application of gene expression profiling is particularly relevant to improving diagnosis, prognosis, and treatment of disease. For example, both the levels and sequences expressed in tissues from subjects with Alzheimer's disease may be compared with the levels and sequences expressed in normal brain tissue.
Alzheimer's disease is a progressive neurodegenerative disorder that is characterized by the formation of senile plaques and neurofibrillary tangles containing amyloid beta peptide. These plaques are found in limbic and association cortices of the brain. The hippocampus is part of the limbic system and plays an important role in learning and memory. In subjects with Alzheimer's disease, accumulating plaques damage the neuronal architecture in limbic areas and eventually cripple the memory process.
Approximately twenty million people worldwide suffer with dementia that results from Alzheimer's disease. The disease can be early onset affecting individuals as young as 30 years of age, or it can be familial or sporadic. Familial Alzheimer's disease was once thought to be inherited strictly as an autosomal dominant trait; however, this view is changing as more genetic determinants are isolated. For example, some normal allelic variants of apolipoprotein E (ApoE), which is found in senile plaques, can either protect against or increase the risk of developing the disease (Strittmatter et al. (1993) Proc Natl Acad Sci 90:1977-1981).
Mutations in four genes are known to predispose an individual to Alzheimer's disease: ApoE, amyloid precursor protein (APP), presenilin-1, and presenilin-2 (Selkoe (1999) Nature 399:A23-A31). The e4 allele of the ApoE gene confers increased risk for late onset Alzheimer's disease. &bgr;-amyloid protein (A&bgr;) is the major component of senile plaques, and it is normally formed when &bgr;- and &ggr;-secretases cleave APP. In Alzheimer's disease patients, large quantities of A&bgr; are generated and accumulate extracellularly in these neuropathological plaques. Efforts to understand the mechanism underlying A&bgr; deposition have recently focused on the APP-cleaving secretases. In fact, two yeast aspartyl proteases have been shown to process APP in vitro (Zhang et al. (1997) Biochim Biophys Acta 1359:110-122). Evidence using peptidomimetic probes further confirms that the secretases are intramembrane-cleaving aspartyl proteases (Wolfe et al. (1999) Biochemistry 38:4720-4727). The presenilin-1 gene is a candidate for the &ggr;-secretase that cleaves the APP carboxyl terminus. Several lines of evidence support the involvement of presenilins in the disease process. Presenilin can be coimmunoprecipitated with APP, and mutations in the presenilin genes increase production of the 42-amino acid peptide form of A&bgr;. These missense point mutations result in a particularly aggressive, early onset form of the disease (Haas and DeStrooper (1999) Science 286:916-919).
The proteases, BACE1 and BACE2 (&bgr;-site APP cleaving enzymes 1 and 2) which appear to be &bgr;-secretases, are potential therapeutic targets because of their ability to cleave APP. Vasser et al. (1999; Science 286:735-741) have found that BACE1 is an aspartyl protease with &bgr;-secretase activity which cleaves APP to produce A&bgr; peptide in vitro. It is expressed at moderate levels across all brain regions and is concentrated in neurons but not in glia. BACE2, which has 52% amino acid identity with BACE1, has been described by Saunders et al. (1999; Science 286:1255a). Whereas BACE1 maps to the long arm of chromosome 11, BACE2 maps to the Down syndrome region of chromosome 21 (Acquati et al. (2000) 468: 59-64; Saunders et al. supra). This location is significant because middle-aged Down syndrome patients have enhanced &bgr;-amyloid deposits. Other members of the BACE family may also participate in this APP cleavage: the amino terminals of A&bgr; peptides appear to be cleaved heterogeneously indicating that there may be several &bgr;-secretases involved in APP processing (Vasser (1999) Science 286:735-741).
Associations between Alzheimer's disease and many other genes and proteins have been reported. Fetal Alzheimer antigen (FALZ) and synuclein a (SNCA) are found in brain plaques and tangles. Inheritance of some gene polymorphisms is also linked to increased risk of developing the disease. For example, a polymorphism in the gene encoding &bgr;2-macroglobulin, a protein that can act as a protease inhibitor, is associated with increased risk for developing a late-onset form of Alzheimer's disease.
The present invention provides for a composition comprising a plurality of cDNAs for use in detecting changes in expression of genes encoding proteins that are associated with Alzheimer's disease. Such a composition can be employed for the diagnosis, prognosis or treatment of Alzheimer's disease and possibly other forms of dementia correlated with differential gene expression. Differential gene expression may also reflect inflammation, proliferation, and glial cell activation which occur secondary to the disease process. The present invention satisfies a need in the art in that it provides a set of differentially expressed genes which may be used entirely or in part to diagnose, to stage, to treat, or to monitor the progression or treatment of a subject with a brain disorder such as Alzheimer's disease.
SUMMARY
The present invention provides a composition comprising a plurality of cDNAs and their complements which are differentially expressed in brain tissues and which are selected from SEQ ID NOs:1-138 as presented in the Sequence Listing. In one embodiment, each cDNA is downregulated at least two-fold, SEQ ID NOs: 1-95; in another embodiment, each cDNA is upregulated at least two-fold, SEQ ID NOs:96-138. In one aspect, the composition is useful to diagnose a brain disorder selected from akathesia, Alzheimer's disease, amnesia, amyotrophic lateral sclerosis, ataxias, bipolar disorder, catatonia, cerebral palsy, cerebrovascular disease Creutzfeldt-Jakob disease, dementia, depression, Down's syndrome, tardive dyskinesia, dystonias, epilepsy, Huntington's disease, multiple sclerosis, muscular dystrophy, neuralgias, rneurofibromatosis, neuropathies, Parkinson's disease, Pick's disease, retinitis pigmentosa, schizophrenia, seasonal affective disorder, senile dementia, stroke, Tourette's syndrome and cancers including adenocarcinomas, melanomas, and teratocarcinomas, particularly of the brain. In another aspect, the composition is immobilized on a substrate.
The invention also provides a high throughput method to detect differential expression of one or more of the cDNAs of the composition. The method comprises hybridizing the substrate comprising the composition with the nucleic acids of a sample, thereby forming one or more hybridization complexes, detecting the hybridization complexes, and comparing the hybridization complexes with those of a standard, wherein differences in the size and signal intensity of each hybridization complex indicates differential expression of nucleic acids in the sample. In o
Edwards Carla M.
Loring Jeanne F.
Tingley Debora W.
Incyte Corporation
Incyte Corporation
Ponnaluri Padmashri
LandOfFree
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