Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-31
2002-11-12
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S418000, C514S447000, C514S566000
Reexamination Certificate
active
06479528
ABSTRACT:
FIELD OF THE INVENTION
The current invention relates to methods for inhibiting and/or reversing tau filament formation or polymerization. This invention also relates to methods for treating certain neurological disorders in vivo by administering pharmaceutical compositions which inhibit and/or reverse tau filament formation or polymerization.
BACKGROUND
The microtubule-associated protein tau is a soluble cytosolic protein that is believed to contribute to the maintenance of the cytoskeleton (Johnson et al.,
Alzheimer's Disease Review
3: 125 (1998); Buee et al.,
Brain Research Reviews
33:95 (2000)). However, in many disease states, tau protein is induced by unknown cellular conditions to self-associate into filamentous structures (Spillantini et al.,
Trends Neurosci.
21: 428 (1998)). These filamentous forms of tau can be found in such varied neurodegenerative disorders as Alzheimer's disease (AD) (Wood et al.,
Proc. Natl. Acad. Sci. USA
83: 4040 (1986); Kosik et al.,
Proc. Natl. Acad. Sci. U.S.A
83: 4044 (1986); Grundke-Iqbal et al.,
J. Biol. Chem.
261: 6084 (1986)), corticobasal degeneration (CBD) (Feany et al.,
Am. J. Pathol.
146: 1388 (1995)), progressive supranuclear palsy (PSP) (Tabaton et al.,
Ann. Neurol.
24: 407 (1988)), Pick's disease (PD) (Murayama et al.,
Ann. Neurol.
27: 394 (1990)), Down syndrome (Papasozomenos et al.,
Lab Invest.
60: 123 (1989)), and frontotemporal dementias and Parkinsonism linked to chromosome 17 (FTDP-17) (Spillantini et al.,
Proc. Natl. Acad. Sci. USA
94: 4113 (1997)). There remains a need for the identification of effective therapies for these neurodegenerative disorders.
There is still debate as to the involvement of tau fibril formation in the onset of neurodegeneration. It is not known whether abnormal tau polymerization causes or modulates the neurodegeneration process or whether it is simply a byproduct of the process. For example, in AD it is hotly debated whether the dementia-causing pathological structures are the amyloid-beta positive senile plaques, the tau-positive neurofibrillary tangles, or a combination of both (Hardy et al.,
Nat. Neurosci.
1: 355 (1998)). In order to understand the etiopathogenesis of AD, there remains a need to identify molecular mechanisms which lead to the polymerization of the pathological structures themselves.
Much of what is currently known regarding tau polymerization stems from in vitro assembly assays. However, with few exceptions, the conditions that have been used to achieve tau polymerization have been extremely nonphysiological. The first experiment describing the self-association of tau protein into AD-like filaments involved 60 hours of incubation in 8M urea (Montejo de Garcini et al.,
J. Biochem.
(Tokyo) 102: 1415 (1987)). Other experiments have required significant truncations of the molecule followed by chemical cross-linking (Wille et al.,
J. Cell. Biol.
118: 573 (1992)), extremely high protein concentrations (40 &mgr;M) (Goedert et al.,
Nature
383: 550 (1996)), incubation periods up to six weeks (Schweers et al.,
Proc. Natl. Acad. Sci. USA
92: 8463 (1995)), or combinations of these techniques. Although relatively mild conditions have been described which result in the polymerization of low concentrations of biochemically purified tau protein (Wilson et al.,
J. Biol. Chem.
270: 24306 (1995)), this process can be greatly enhanced by the addition of polyanionic compounds under oxidative conditions (Goedert et al.,
Nature
383: 550 (1996); Kampers et al.,
FEBS Lett.
399: 344 (1996); Hasegawa et al.,
J. Biol. Chem.
272: 33118 (1997); Friedhoff et al.,
Biochemistry
37: 10223 (1998); Friedhoff et al.,
Proc. Natl. Acad. Sci. USA
95: 15712 (1998); Nacharaju et al.,
FEBS Lett.
447: 195 (1999)) and the addition of free fatty acids under reducing conditions (Nacharaju et al.,
FEBS Lett.
447: 195 (1999); Wilson et al.,
Am. J. Pathol.
150: 2181 (1997); King et al.,
Biochemistry
38: 14851 (1999); King et al.,
J. Neurochem.
74: 1749 (2000); Gamblin. et al.,
Biochemistry
39: 6136 (2000)). However, there remains a need to identify improved methods for further enhancing the polymerization of tau protein in vitro in order to help facilitate the identification of reagents which can be used to treat diseases involving tau polymerization in vivo.
Various in vitro polymerization techniques have been used to investigate the in vitro polymerization of tau. For example, it has been shown that the fatty acid induction of tau polymerization proceeds through a ligand-dependent mechanism under reducing conditions (King et al.,
Biochemistry
38: 14851 (1999)). Another set of experiments showed that, contrary to expectations, extensive phosphorylation of the tau molecule with various protein kinases inhibited the polyanion induction of polymerization (Schneider et al.,
Biochemistry
38: 3549 (1999)). Some of the factors leading to tau polymerization in the disease state are now being studied. As mentioned above, extensive tau pathology is observed in a class of neurodegenerative disorders called FTDP-17. These disease states have been linked to mutations in the tau gene that lead to missense point mutations or changes in the isoform expression of the tau protein. In vitro experiments have shown that several of the single amino acid missense point mutations found in FTDP-17 can lead to increased filament formation (Nacharaju et al.,
FEBS Lett.
447: 195 (1999); Gamblin et al.,
Biochemistry
39: 6136 (2000); Goedert et al.,
Nat. Med.
5: 454 (1999)). It has also been shown that tau isoforms have different polymerization characteristics, which could lead to increased tau pathology in cases of FTDP-17 with altered isoform compositions (King et al.,
J. Neurochem.
74: 1749 (2000)). However, a strong link between the risk factors associated with the most common neurodegenerative disorder, AD, and increased tau polymerization has not been established. Therefore, there remains a need to identify AD risk factors that are associated with tau polymerization in order to accelerate the development of effective AD therapies.
A number of risk factors have been identified which have the common characteristic of being potential contributors to oxidative stress. Thus, oxidative stress may play a major role in the etiology of Alzheimer's disease (AD). The normal aging process, head trauma, increased levels of heavy metals (e.g., Fe, Al, Hg), and, especially in the case of AD, aggregation of the &bgr;-amyloid protein (A&bgr;) are all thought to be potential contributors to increased oxidative stress. In the oxidative stress hypothesis for AD, free radicals generated by these risk factors, possibly in the form of reactive oxygen species, would then attack biological molecules that are sensitive to oxidation, such as proteins, DNA, and lipids/fatty acids, causing a cascade that would eventually lead to neurodegeneration (see, e.g., Markesbery et al.,
Free Radic. Biol. Med.
23: 134 (1997)).
There is direct evidence that sensitive molecules in vulnerable AD brains are modified by oxidative stress. Free radicals can lead to the carbonyl derivatization of enzymes such as glutamine synthetase and creatine kinase. This process is quickly followed by protease degradation of the enzymes. DNA is also sensitive to oxidative stress. Increases in the adduct 8-hydroxy-2′-deoxyguanisine have been reported for mitochondrial DNA, and to a lesser extent nuclear DNA, in AD brains when compared to age-matched controls. In addition, a two-fold increase in oxidative damage to DNA through strand breaks has been described in the brains of AD patients (see, e.g., Markesbery et al.,
Free Radic. Biol. Med.
23:134 (1997)).
Polyunsaturated fatty acids (FA) are especially vulnerable to oxidative stress since their double bonds make the removal of H+ by free radicals relatively easy. Although some reports disagree on the location of FA oxidation in AD brain (see, e.g., Markesbery,
Brain Pathol.
9: 133 (1999)), it is clear that thiobarbituric acid reactive substances (a marker
Khatami Sam
Kuret Jeff
Fitch Even Tabin & Flannery
Jarvis William R. A.
Neuronautics, Inc.
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