Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or...
Reexamination Certificate
1999-02-02
2002-10-29
Crouch, Deborah (Department: 1632)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
C435S007100
Reexamination Certificate
active
06472140
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the field of medical genetics. More specifically, the invention provides for therapeutic agents for Alzheimer's Disease and methods of screening for therapeutic agents for Alzheimer's disease that are based on affecting alpha-2-macroglobulin function and expression.
2. Related Art
Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects more than 4 million people per year in the US (Döbeli, H.,
Nat. Biotech.
15:223-24 (1997)). It is the major form of dementia occurring in mid to late life: approximately 10% of individuals over 65 years of age, and approximately 40% of individuals over 80 years of age, are symptomatic of AD (Price, D. L., and Sisodia, S. S.,
Ann. Rev. Neurosci.
21:479-505 (1998)).
The first recognized clinical symptom of AD is usually the loss of short-term memory (Schellenberg, G. D.,
Proc. Nati. Acad Sci. USA
92:8552-559 (1995)). Other common symptoms include abnormal judgement and behavior, and difficulty with language, orientation, problem solving, calculations, and visuospacial perception (Price, D. L., and Sisodia, S. S.,
Ann. Rev. Neurosci.
21:479-505 (1998); Schellenberg, G. D.,
Proc. Natl. Acad. Sci. USA
92:8552-559 (1995)). These symptoms often worsen until cognitive function is almost entirely lost, and the patient cannot function independently (Schellenberg, G. D.,
Proc. Natl. Acad. Sci. USA
92:8552-559 (1995); Price, D. L., and Sisodia, S. S.,
Ann. Rev. Neurosci.
21:479-505 (1998)). By late stages of the disease patients typically lack verbal ability, cannot recognize people, and are incontinent and bed-ridden (Price, D. L., and Sisodia, S. S.,
Ann. Rev. Neurosci.
21:479-505 (1998); Sloane, P. D.,
Am. Family Phys.
58: 1577-86 (1998)).
Known risk factors for AD include age, genetic predisposition, abnormal protein (&bgr;-amyloid) deposition in the brain, and certain environmental factors such as head injury, hypothyroidism, and a history of depression. The majority of AD patients do not exhibit symptoms until their seventies (Price, D. L., and Sisodia, S. S.,
Ann. Rev. Neurosci.
21:479-505 (1998)). However, individuals who have inherited particular genetic defects often exhibit symptoms in midlife (Price, D. L., and Sisodia, S. S.,
Ann. Rev. Neurosci.
21:479-505 (1998)). This latter type of AD, called early-onset familial AD (FAD), accounts for 5-10% of AD cases, and has been linked to defects in three different genes, APP, PSEN1, PSEN2 (Blacker, D. and Tanzi, R. E.,
Archives of Neurology
55:294-296 (1998)). Mutations in these genes lead to increased production of the amyloidogenic &bgr;-amyloid peptide (A&bgr;) (Citron, M., et al,
Nature Medicine
3:67-72 (1997); Suzuki, N., et al.,
Science
264:1336-1340 (1994)).
The most prevalent form of AD, called late-onset AD (LOAD), accounts for approximately 90% of AD cases, and has been genetically linked to APOE and LRP (Kang, D. E., et al.,
Neurology
49:56-61 (1997); Kounnas, M. Z., el al.,
Cell
82:331-340 (1995)). Recently, another gene, the alpha-2-macroglobulin gene (A2M), was found to be linked to LOAD (Blacker, D., et al.,
Nature Genetics
19:357-360 (1998)). Carriers of a particular mutation in A2M were discovered to be at increased risk of AD. This mutation is a pentanucleotide deletion at the 5′ splice site of the second exon encoding the bait region of alpha-2-macroglobulin (&agr;
2
M), and is referred to as the A2M-2 genotype. The A2M-2 genotype is present in 30% of the population (Blacker, D., et al.,
Nature Genetics
19:357-360 (1998)). The A2M-2 pentanucleotide deletion is a predisposing factor for AD.
Presently, there is no cure for AD on the horizon and its incidence is increasing as the population ages (Price, D. L., and Sisodia, S. S.,
Ann. Rev. Neurosci.
21:479-505 (1998)). Due to the lateness in life of the onset of AD symptoms, the ability to delay onset by as little as 5 years could decrease the number of AD patients by as much as 50% (Marx, J.,
Science
273:50-53 (1996)). With the large number of people already affected, and projected to be affected by AD, a drug that could merely delay the onset of AD would be very valuable.
Therapeutic agents based on predisposing factors of AD might be able to prevent, delay or slow progression of the disease. However, presently, available treatments are primarily aimed at treatment of the symptoms of the disease (Enz, A., “Classes of drugs,” in: Pharmacotherapy of Alzheimer's Disease, Gauthier, S., ed., Martin Dunitz, publ., Malden, Mass. (1998)). These AD drugs offer only modest success, and at most, merely slow the progression of the disease (Delagarza, V. W.,
Am. Family Phys.
58:1175-1182 (1998); Enz, A., “Classes of drugs,” in: Pharmacotherapy of Alzheimer's Disease, Gauthier, S., ed., Martin Dunitz, publ., Malden, Mass. (1998)). Presently approved and investigational drugs for treating AD can be characterized as those whose actions enhance neurotransmitter effect, or those believed to protect neurons (Delagarza, V.,
Am. Family Phys.
58:1175-1182 (1998)). The most well known drugs in the first category are the cholinesterase inhibitors, such as tacrine (Cognex™) and doneprezil (Aricept™), both of which have been approved by the FDA (Delagarza, V.,
Am. Family Phys.
58:1175-1182 (1998); Sloan, P.,
Am. Family Phys.
58:1577-1586 (1998)). Tacrine and doneprezil are only modestly effective (Sloan, P.,
Am. Family Phys.
58:1577-1586 (1998)), and are associated with unpleasant side effects including nausea and vomiting (Delagarza, V.,
Am. Family Phys.
58:1175-1182 (1998)). Several neuro-protective drugs are under investigation for the treatment of AD, including estrogen, vitamin E, selegiline and non-steroidal anti-inflammatory drugs (NSAIDs) (Sloan, P.,
Am. Family Phys.
58:1577-1586 (1998); Delagarza, V.,
Am. Family Phys.
58:1175-1182 (1998)). None of these drugs have been approved yet for the treatment of AD, and each has significant drawbacks, including negative side-effects, or association with increased risk of other diseases. (Sloan, P.,
Am. Family Phys.
58:1577-1586 (1998); Delagarza, V.,
Am. Family Phys.
58:1175-1182 (1998); Enz, A., “Classes of drugs,” in: Pharmacotherapy of Alzheimer's Disease, Gauthier, S., ed., Martin Dunitz, publ., Malden, Mass. (1998)).
Thus, there is a need for new AD therapeutic agents, especially those based on predisposing factors of AD. In addition, there is a need for drug screening systems to aid in developing these therapeutic agents.
SUMMARY OF THE INVENTION
Based on the finding, described herein, that the A2M-2 deletion leads to the production of altered &agr;
2
M RNA transcripts and proteins, strategies aimed at replacing or supplementing normal &agr;
2
M function and activities, and/or at suppressing defective &agr;
2
M function in the brain may serve as a means for therapeutically preventing, treating, or even reversing AD neuropathogenesis. In addition, these strategies may be useful for treating other pathologies associated with defective &agr;
2
M function. Moreover, methods described herein may be used to screen for these therapeutic agents. Thus, the invention provides for new therapeutic agents for AD, for pharmaceutical compositions containing these therapeutic agents, for methods of using these therapeutic agents, and for methods of screening for these therapeutic agents.
The first aspect of the invention is to provide for a therapeutic agent for Alzheimer's Disease, where the agent can replace or supplement &agr;2M function, or can suppress the expression of A2M-2. A molecule that can bind to A&bgr; and to LRP may be able to promote clearance of A&bgr; through LRP mediated endocytosis. Thus, one embodiment of the invention is an anti-LRP-A&bgr; molecule having an A&bgr; binding domain, and an LRP binding domain. In a preferred embodiment of the invention, this molecule is a peptide.
In one embodiment of the invention the peptide is an anti-LRP-A&bgr; peptide having an A&bgr; binding domain composed o
Kovacs Dora
Saunders Aleister J.
Tanzi Rudolph E.
Crouch Deborah
Sterne Kessler Goldstein & Fox P.L.L.C.
The General Hospital Corporation
Woitach Joseph
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