Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
1999-09-24
2001-02-06
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
C424S009100, C435S018000, C435S071100, C435S004000, C530S202000, C800S008000, C514S012200, C514S021800, C436S501000, C436S086000, C930SDIG722, C536S023100
Reexamination Certificate
active
06184351
ABSTRACT:
BACKGROUND OF THE INVENTION
Parkinson's disease (PD) is a progressive, degenerative neurologic disorder which usually occurs in late mid-life, and is the second most common neurodegenerative disorder, after Alzheimer's disease. PD predominantly affects dopaminergic neurons in the nigrastriatal system but also several other regions of the brain, and is clinically characterized by bradykinesia, tremor, and rigidity.
Bradykinesia, a slowness or “poverty” of movement, slows the pace of such ultilitarian activities as walking and eating, and also makes movements that were once second nature take on a ponderous and deliberate quality. Tremor is a shakiness that generally affects limbs that are not otherwise in motion. For those PD patients diagnosed at a relatively young age, tremor is reported as the most disabling symptom. Older patients say their greatest challenge is walking or keeping their balance. Rigidity is caused by the inability of muscles to relax as opposing muscle groups contract, causing tension which can produce aches and pains in the back, neck, shoulders, temples, or chest.
PD is pathologically characterized by nerve cell loss in the substantia nigra and by the presence of intracytoplasmic Lewy bodies. A presynaptic protein, called &agr;-synuclein, has been detected in Lewy bodies and shown to be the major filamentous component in Lewy bodies in PD; Spillantini et al.,
Proc. Natl. Acad. Sci.,
95:6469-6473 (1998).
Synuclein was originally cloned and identified as a synaptic protein in torpedo; Maroteaux et al.,
J. Neurosci.,
8:2804-2815 (1988) and later bovine; Nakjo et al.,
Eur. J. Biochem.,
217:1057-1063 (1993), rat; Maroteaux et al.,
Mol. Brain Res.,
11:335-343 (1991), and human (precursor of the non-A&bgr; component of Alzheimer's disease amyloid(NACP)); Ueda et al.,
Proc. Natl. Aca. Sci. USA,
90:11282-11286 (1993). Subsequent studies showed that there are two types of synucleins, &agr; and &bgr;, and NACP is analogous to &agr;-synuclein; Iwai et al.,
Neuron,
14:467-475 (1994). The function of &agr;-synuclein is unknown, but two naturally occurring mutations in &agr;-synuclein, A53T and A30P, have been linked to familial early-onset PD; Polymeropoulos, et al.,
Science,
276:2045-2047 (1997); Kruger et al.,
Nat. Genet.,
18:106-108 (1998).
Baba et al.,
Am. J. Pathol.,
152:879-884 (1998) reported data strongly implicating &agr;-synuclein in the selective degeneration of neurons in sporadic PD. Baba et al. suggest that the mechanisms leading to the selective incorporation of &agr;-synuclein into Lewy bodies probably involve alterations in the metabolism of &agr;-synuclein that render it insoluble and prone to aggregation. Baba et al. thus postulate that wild type &agr;-synuclein probably plays a role in the pathogenesis of sporadic PD, and that the A53T substitution in &agr;-synuclein may augment the process.
Conway et al.,
Nature Medicine,
4:1318-1320 (1998) then reported that the naturally occurring &agr;-synuclein mutations, A53T and A30P, may promote PD pathogenesis by accelerating &agr;-synuclein fibril formation, which may be an early step in Lewy body formation. Conway et al. utilize an in vitro fibrillization assay; Harper et al.,
Ann. Rev. Biochem.,
66:385-407 (1997), and present data demonstrating that both mutant forms, at high concentrations, form Lewy body-like fibrils and discrete spherical assemblies; most rapidly by the A53T mutant. Based on their findings, Conway et al. postulate that inhibiting &agr;-synuclein fibrillization may be an effective therapeutic strategy against the disease. Conway et al. also state that the in vitro fibrillization assay may allow compound libraries to be screened to identify such &agr;-synuclein fibrillization inhibitors.
Despite these reports and other extensive PD research conducted to date, there is still no known cure for PD. Deprenyl (selegiline), begun early in the disorder, can slow progression of the disease, and there is also evidence that “antioxidants” such as vitamin E and selenium may be of some benefit. There clearly exists the need for improved means of diagnosis and treatment of PD.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to address this need by providing artificial &agr;-synuclein super-mutants which demonstrate accelerated aggregation as compared to naturally occurring mutants and which can be utilized for transgenic animal production, and subsequent generation of the first progressive PD model.
Also provided is an in vitro aggregation assay which can be used to evaluate &agr;-synuclein super-mutants, and which can be formatted to allow for the high throughput screening for &agr;-synuclein nucleation inhibitors for the treatment of PD.
REFERENCES:
Lewy, F.H.,Handbuch Der Neurologie“Pathologische Anatomie” (ed. Lewandowski, M.) 920-933, (Springer, Berlin, 1912).
Forno, L.S.Journal of Neuropathology and Experimental Neurology“Neuropathology of Parkinson's Disease” vol. 55, 259-272, (1996).
Pollanen, M.S., et al.Journal of Neuropathology and Experimental Neurology“Pathology and Biology of the Lewy Body” vol. 52, 183-191, (1993).
Spillantini, G.M., et al.Proc. Natl. Acad. Science USA&agr;-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and Dementia with Lewy Bodies: vol. 95, 6469-6473, (May 1998).
Krüger, R., et al.Nature Genetics“Ala30Pro mutation in the gene encoding a-synuclein in Parkinson's disease” vol. 18, 106-108, (Feb. 1998).
Polymeropoulos, M. H., et al.Science“Mutation in the &agr;-Synuclein Gene Identified in Families with Parkinson's Disease” vol. 276, 2045-2047, (Jun. 1997).
Spillantini, M.G., et al.Nature“&agr;-Synuclein in Lewy Bodies” vol. 388, 839-840, (Aug. 1997).
Takeda, A., et al.American Journal of Pathology“Abnormal Accumulation of NACP/&agr;-Synuclein in Neurodegenerative Disorders” vol. 152, 367-372, (Feb. 1998).
Baba, M., et al.American Journal of Pathology“Aggregation of &agr;-Synuclein in Lewy Bodies of Sporadic Parkinson's Disease and Dementia with Lewy Bodies” vol. 152,879-884, (Apr. 1998).
Uéda, K., et al.Proc. Natl. Acad. Science USA“Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease” vol. 90, 11282-11286, (Dec. 1993).
Weinreb, P.H., et al.Biochemistry“NACP, A Protein Implicated in Alzheimer's Disease and Learning, Is Natively Unfolded” vol. 35, 13709-13715, (Oct. 1996).
Jarrett, J.T., et al.CellSeeding “One-dimensional Crystallization of Amyloid: A Pathogenic mechanism in Alzheimer's Disease and Scrapie?” vol. 73, 1055-1058, (Jun. 1993).
Lacey, D.L., et al.Cell“Osteoprotegerin Ligand is a Cytokine that Regulates Osteoclast Differentiation and Activation” vol. 93, 165-176, (Apr. 1998).
Dong, A., et al.Biochemistry“Secondary Structure of the Pentraxin Female Protein in Water Determined by Infrared Spectroscopy: Effects of Calcium and Phosphorylcholine” vol. 31, 9364-9370, (Jul. 1992).
Biere Anja Leona
Citron Martin
Amgen Inc.
Crandall Craig A.
Levy Ron K.
Low Christopher S. F.
Odre Steven M.
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