Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-11-02
2004-09-07
Kemmerer, Elizabeth (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S017400, C514S018700, C530S300000, C530S329000
Reexamination Certificate
active
06787519
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to apolipoprotein E, and in particular to methods of treating disorders relating to ApoE.
BACKGROUND OF THE INVENTION
Human apolipoprotein (apo) E has three major isoforms, apoE2, apoE3, and apoE4 (for review see Mahley and Huang (1999)
Curr. Opin. Lipidol.
10:207-217). It has been established that apoE4 is associated with increased plasma cholesterol levels and higher risk for the development of coronary heart disease. Dallongeville (1992)
J. Lipid Res.
33:447-454. ApoE4 has also been linked to the pathogenesis of Alzheimer's disease. The apoE4 allele is a major risk factor or susceptibility gene associated with approximately 40-65% of cases of sporadic and familial Alzheimer's disease and it increases the occurrence and lowers the age of onset of the disease. Corder et al. (1993)
Science
261:921-923. In addition, the apoE4 allele is also associated with poor clinical outcome in patients with acute head trauma and stroke. Slooter et al. (1997) JAMA 277:818-821; and Nicoll et al. (1996)
Neuropathol. Appl. Neurobiol.
22:515-517.
The neuropathological hallmarks of Alzheimer's disease are the presence of neuritic amyloid plaques and neurofibrillary tangles in the brain. Selkoe (1991)
Neuron
6:487-498; and Roses, et al. (1994)
Curr. Opinion Biotechnol.
5:663-667. The neuritic plaques represent extracellular deposits of amyloid. The major component of the deposits is the amyloid beta (A&bgr;) peptide (DS487), which is the proteolytic product of the amyloid precursor protein (APP). In contrast to amyloid plaques, neurofibrillary tangles are primarily intracellular deposits composed largely of highly phosphorylated microtubule-associated protein, tau (p-tau), and, to a lesser extent, phosphorylated NF—H (p-NF—H). ApoE is found in both amyloid plaques and the neurofibrillary tangles
There are many hypotheses to explain the association of apoE4 allele with the development of Alzheimer's disease, including its modulation of amyloid &bgr; (A&bgr;) deposition or clearance in the brain, and a lack of interaction of apoE4 with the microtubule-associated protein, tau, which binds to and stabilizes microtubules.
Alzheimer's disease is an insidious and progressive neurological disorder for which there is currently no cure. In view of the lack of adequate treatment for Alzheimer's disease, there exists a need for novel treatment methods for this neurological disorder. The instant invention provides methods of treating disorders relating to ApoE4, and methods of reducing neurofibrillary tangles associated with Alzheimer's disease.
Literature
Huang et al. (2001)
Proc. Natl. Acad. Sci. USA
98:8838-8843; U.S. Pat. No. 6,046,381.
SUMMARY OF THE INVENTION
The present invention provides methods inhibiting formation of neurofibrillary tangles; and methods for treating disorders relating to apolipoprotein E (apoE) in a subject. The methods generally involve reducing the level of a carboxyl-terminal truncated form of apoE in a neuronal cell of a subject. The invention further provides isolated cells comprising a nucleic acid molecule encoding a carboxyl-terminal truncated form of apoE; and methods of screening compounds using the cells. The invention further provides compounds that inhibit an apoE cleavage enzyme, and that reduce the formation of neurofibrillary tangles in a neuronal cell. The invention further provides transgenic non-human animals that include as a transgene a nucleic acid that encodes a carboxyl-terminal truncated form of apoE; as well as methods of screening compounds using transgenic animals.
REFERENCES:
patent: 5610297 (1997-03-01), Powers
patent: 6046381 (2000-04-01), Mucke et al.
patent: WO 98/01101 (1988-01-01), None
Bi et al. (Jul. 17, 2001) “Rapid induction of intraneuronal neurofibrillary tangles in Apolipoprotein E-deficient mice.” PNAS 98(15 8832-8837.*
Kopito (Dec. 2000) “Aggresomes, inclusion bodies and protein aggregation.” Trends Cell Biol. 10(12):524-30.*
Ljundberg et al. (May 7, 2002) “Truncated apoE forms tangle-like structures in a neuronal cell line.” Molecular Neuroscience 13(6): 867-870.*
Tolar et al. (Aug. 15, 1999) Truncated Apolipoprotein E (ApoE) Causes Increased Intracellular Calcium and May Mediate ApoE Neurotoxicity. J Neurosci. 19(16):7100-7110.*
Sigma Chemical Company, Product Detail Antipain hydrochloride Product No. A6191.*
Huang, Y. et al., Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. PNAS, 2001, vol. 98, No. 15, pp. 8838-8843.
Emilien, G. et al., Alzheimer Disease Mouse Models pave the way for therapeutic opportunities. Neurological Review, 2000, vol. 57, pp. 176-181.
Huang Y. et al., Bioactive fragments of apolipoprotein E induce neurofibrillary tangles in cultured neurons. Society for Neuroscience Abstracts, 2000, vol. 26, No. 1-2, 202.8.
Mahley and Huang (1999)Curr. Opin. Lipidol. 10:207-217.
Dallongeville (1992)J. Lipid Res. 33:447-454.
Slooter et al. (1997) JAMA 277 :818-821.
Nicoli et al. (1996)Neuropathol. Appl. Neurobiol. 22:515-517.
Selkoe (1991)Neuron6:487-498.
Roses, et al. (1994)Curr. Opinion Biotechnol. 5:663-667.
Huang et al. (2001)Proc. Natl. Acad. Sci. USA98:8838-8843.
Huang Yadong
Mahley Robert W.
Borden Paula A.
Bozicevic Field & Francis LLP
Kemmerer Elizabeth
Nichols Christopher James
The Regents of the University of California
LandOfFree
Methods of treating disorders related to apoE does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods of treating disorders related to apoE, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods of treating disorders related to apoE will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3238265