Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Polymer from ethylenic monomers only
Reexamination Certificate
1999-09-28
2002-07-16
Levy, Neil S. (Department: 1616)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Polymer from ethylenic monomers only
C424S078350, C424S078360, C424S078370, C424S078380, C424SDIG001
Reexamination Certificate
active
06419916
ABSTRACT:
FIELD OF THE INVENTION
The present invention is related generally to assays and more specifically to assays which determine compounds which might provide a therapeutic effect of a disease associated with a conformationally altered protein.
BACKGROUND OF THE INVENTION
There are a considerable number of diseases associated with a conformationally altered protein. For example, Alzheimer's disease is associated with APP, A&bgr; peptide, &agr;1-antichymotrypin, tau and non-A&bgr; component. Many of these diseases are neurological diseases. However, type II Diabetes is associated with Amylin and Multiple myeloma-plasma cell dyscrasias is associated with IgGL-chain. The relationship between the disease onset and the transition from the normal protein to the conformationally altered protein has been examined very closely in some instances such as with the association between prion diseases and PrP
Sc
.
Prion diseases are a group of fatal neurodegenerative disorders that can occur in hereditary, sporadic, and infectious forms (Prusiner, S. B. Scrapie prions.
Annu. Rev. Microbiol
. 43, 345-374 (1989)). These illnesses occur in humans and a variety of other animals (Prusiner, S. B. Prions.
Proc. Natl. Acad. Sci
. USA 95, 13363-13383 (1998)). Prions are infectious proteins. The normal, cellular form of the prion protein (PrP) designated PrP
C
contains three &agr;- helices and has little &bgr;- sheet; in contrast, the protein of the prions denoted PrP
Sc
is rich in &bgr;-sheet structure. The accumulation of PrP
Sc
in the central nervous system (CNS) precedes neurologic dysfunction accompanied by neuronal vacuolation and astrocytic gliosis.
The spectrum of human prion diseases includes kuru (Gajdusek, D. C., Gibbs, C. J., Jr. & Alpers, M. Experimental transmission of a kuru-like syndrome to chimpanzees.
Nature
209, 794-796 (1966)), Creutzfeldt-Jakob disease (CJD) (Gibbs, C. J., Jr., et al. Creutzfeldt-Jakob disease (spongiform encephalopathy): transmission to the chimpanzee.
Science
161, 388-389 (1968)), Gerstmann-Sträussler-Scheinker disease (GSS) and fatal familial insomnia (FFI) (Goldfarb, L. G., et al. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism.
Science
258, 806-808 (1992); Medori, R., et al. Fatal familial insomnia: a second kindred with mutation of prion protein gene at codon 178
. Neurology
42, 669-670 (1992)), and a new form of human prion disease, new variant CJD (nvCJD), which has emerged in Great Britain and France (Will, R. G., et al. A new variant of Creutzfeldt-Jakob disease in the UK.
Lancet
347, 921-925 (1996); Cousens, S. N., Vynnycky, E., Zeidler, M., Will, R. G. & Smith, P. G. Predicting the CJD epidemic in humans.
Nature
385, 197-198 (1997); Will, R. G., et al. Deaths from variant Creutzfeldt-Jakob disease.
Lancet
353, 979 (1999)). Several lines of evidence have suggested a link between the nvCJD outbreak and a preceding epidemic of bovine spongiform encephalopathy (BSE) (Will, R. G., et al. A new variant of Creutzfeldt-Jakob disease in the UK.
Lancet
347, 921-925 (1996); Bruce, M. E., et al. Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent.
Nature
389, 498-501 (1997); Hill, A. F., et al. The same prion strain causes vCJD and BSE.
Nature
389, 448-450 (1997); Lasmézas, C. I., et al. BSE transmission to macaques.
Nature
381, 743-744 (1996)). Although it is too early to predict the number of nvCJD cases that might eventually arise in Great Britain and elsewhere (Cousens, S. N., Vynnycky, E., Zeidler, M., Will, R. G. & Smith, P. G. Predicting the CJD epidemic in humans.
Nature
385, 197-198 (1997)), it is clear that effective therapeutics for prion diseases are urgently needed. Unfortunately, although a number of compounds including amphotericins, sulfated polyanions, Congo red dye, and anthracycline antibiotics have been reported as prospective therapeutic agents (Ingrosso, L., Ladogana, A. & Pocchiari, M. Congo red prolongs the incubation period in scrapie-infected hamsters.
J. Virol
. 69, 506-508 (1995); Tagliavini, F., et al. Effectiveness of anthracycline against experimental prion disease in Syrian hamsters.
Science
276, 1119-1122 (1997); Masullo, C., Macchi, G., Xi, Y. G. & Pocchiari, M. Failure to ameliorate Creutzfeldt-Jakob disease with amphotericin B therapy.
J. Infect. Dis
. 165, 784-785 (1992); Ladogana, A., et al. Sulphate polyanions prolong the incubation period of scrapie-infected hamsters.
J. Gen. Virol
. 73, 661-665 (1992)), all have demonstrated only modest potential to impede prion propagation, and none have been shown to effect the removal of pre-existing prions from an infected host.
The PrP gene of mammals expresses a protein which can be the soluble, non-disease form PrP
C
or be converted to the insoluble, disease form PrP
Sc
. PrP
C
is encoded by a single-copy host gene [Basler, Oesch et al. (1986)
Cell
46:417-428] and when PrP
C
is expressed it is generally found on the outer surface of neurons. Many lines of evidence indicate that prion diseases result from the transformation of the normal form of prion protein (PrP
C
) into the abnormal form (PrP
Sc
). There is no detectable difference in the amino acid sequence of the two forms. However, PrP
Sc
when compared with PrP
C
has a conformation with higher &bgr;-sheet and lower &agr;-helix content (Pan, Baldwin et al. (1993)
Proc Natl Acad Sci USA
90:10962-10966; Safar, Roller et al. (1993)
J Biol Chem
268:20276-20284). The presence of the abnormal PrP
Sc
form in the brains of infected humans or animals is the only disease-specific diagnostic marker of prion diseases.
PrP
Sc
plays a key role in both transmission and pathogenesis of prion diseases (spongiform encephalopathies) and it is a critical factor in neuronal degeneration (Prusiner (1997) The Molecular and Genetic Basis of Neurological Disease, 2nd Edition: 103-143). The most common prion diseases in animals are scrapie of sheep and goats and bovine spongiform encephalopathy (BSE) of cattle (Wilesmith and Wells (1991)
Curr Top Microbiol Immunol
172:21-38). Four prion diseases of humans have been identified: (1) kuru, (2) Creutzfeldt-Jakob Disease (CJD), (3) Gerstmann-Sträussler-Sheinker Disease (GSS), and (4) fatal familial insomnia (FFI) [Gajdusek (1977)
Science
197:943-960; Medori, Tritschler et al. (1992)
N Engl J Med
326:444-449]. Initially, the presentation of the inherited human prion diseases posed a conundrum which has since been explained by the cellular genetic origin of PrP.
The assembly and misassembly of normally soluble proteins into conformationally altered proteins is thought to be a causative process in a variety of other diseases. Structural conformational changes are required for the conversion of a normally soluble and functional protein into a defined, insoluble state. Examples of such insoluble protein include: A&bgr; peptide in amyloid plaques of Alzheimer's disease and cerebral amyloid angiopathy (CAA); &agr;-synuclein deposits in Lewy bodies of Parkinson's disease, tau in neurofibrillary tangles in frontal temporal dementia and Pick's disease; superoxide dismutase in amyotrophic lateral sclerosis; huntingtin in Huntington's disease; and prions in Creutzfeldt-Jakob disease (CJD): (for reviews, see Glenner et al. (1989)
J. Neurol. Sci
. 94:1-28; Haan et al. (1990)
Clin. Neurol. Neurosurg
. 92(4):305-310).
Often these highly insoluble proteins form aggregates composed of nonbranching fibrils with the common characteristic of a &bgr;-pleated sheet conformation. In the CNS, amyloid can be present in cerebral and meningeal blood vessels (cerebrovascular deposits) and in brain parenchyma (plaques). Neuropathological studies in human and animal models indicate that cells proximal to amyloid deposits are disturbed in their normal functions (Mandybur (1989)
Acta Neuropathol
. 78:329-331; Kawai et al. (1993)
Brain Res
. 623:142-6; Martin et al. (1994)
Am. J. Pathol
. 145:1348-1381; Kalaria et al. (1995)
Neuroreport
6:477-80; Masl
Prusiner Stanley B.
Scott Michael R.
Supattapone Surachai
Bozicevic Karl
Bozicevic Field & Francis LLP
Levy Neil S.
The Regents of the University of California
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