Clearance and inhibition of conformationally altered proteins

Details Clearance and inhibition of conformationally altered proteins Clearance and inhibition of conformationally altered proteins

1999-06-01

2001-04-10

Levy, Neil S. (Department: 1616)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Biocides; animal or insect repellents or attractants

C424S438000, C424S442000, C424S484000, C424SDIG001, C424S078320, C424S078350, C424S078360, C424S078370, C424S078380, C514S772300, C514S772400, C514S772500, C514S772600, C514S772700

Reexamination Certificate

active

06214366

ABSTRACT:

FIELD OF THE INVENTION
The present invention is related generally to compounds for the treatment of degenerative diseases and to methods of use of such compounds.
BACKGROUND OF THE INVENTION
The assembly and misassembly of normally soluble proteins into conformationally altered proteins is thought to be a causative process in a variety of diseases including the prion diseases, the amyloidoses, and other common degenerative 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 Glenmer 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, fibrillar proteins 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; Masliah et al. (1996)
J. Neurosci.
16:5795-5811). Other studies additionally indicate that amyloid fibrils may actually initiate neurodegeneration (Lendon et al. (1997)
J. Am. Med Assoc.
277:825-3 1; Yankner (1996)
Nat. Med.
2:850-2; Selkoe (1996)
J. Biol. Chem.
271:18295-8; Hardy (1997)
Trends Neurosci.
20:154-9).
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 (spongiforn 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 i 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.
In both AD and CAA, the main amyloid component is the arnyloid &bgr; protein (A&bgr;).
The A&bgr; peptide, which is generated from the amyloid &bgr; precursor protein (APP) by two putative secretases, is present at low levels in the normal CNS and blood. Two major variants, A&bgr;
1-40
and A&bgr;
1-42
, are produced by alternative carboxy-terminal truncation of APP (Selkoe et al.(1988)
Proc. Natl. Acad. Sci. USA
85:7341-7345; Selkoe, (1993)
Trends Neurosci
16:403-409). A&bgr;
1-42
is the more fibrillogenic and more abundant of the two peptides in amyloid deposits of both AD and CAA. In addition to the amyloid deposits in AD cases described above, most AD cases are also associated with amyloid deposition in the vascular walls (Hardy (1997), supra; Haan et al. (1990), supra; Terry et al., supra; Vinters (1987), supra; Itoh et al. (1993), supra; Yamada et al. (1993), supra; Greenberg et al. (1993), supra; Levy et al. (1990), supra). These vascular lesions are the hallmark of CAA, which can exist in the absence of AD.
Human transthyretin (TTR) is a normal plasma protein composed of four identical, predominantly &bgr;-sheet structured units, and serves as a transporter of hormone thyroxin. Abnormal self assembly of TTR into amyloid fibrils causes two forms of human diseases, namely senile systemic amyloidosis (SSA) and familial amyloid polyneuropathy (FAP) (Kelly (1996)
Curr Opin Strut Biol
6(1):11-7). The cause of amyloid formation in FAP are point mutations in the TTR gene; the cause of SSA is unknown. The clinical diagnosis is established histologically by detecting deposits of amyloid in situ in bioptic material.
To date, little is known about the mechanism of TTR conversion into amyloid in vivo. However, several laboratories have demonstrated that amyloid conversion may be simulated in vitro by partial denaturation of normal human TTR [McCutchen, Colon et al. (1993)
Biochemistry
32(45):12119-27; McCutchen and Kelly (1993)
Biochem Biophys Res Commun
197(2) 415-21]. The mechanism of conformational transition involves monomeric conformational intermediate which polymerizes into linear &bgr;-sheet structured amyloid fibrils [Lai, Colon et al. (1996)
Biochemistry
35(20):6470-82]. The process can be mitigated by binding with stabilizing molecules such as thyroxin or triiodophenol (Miroy, Lai et al. (1996) Proc Natl Acad Sci USA 93(26):15051-6).
The precise mechanisms by which neuritic plaques are formed and the relationship of plaque formation to the disease-associated neurodegenerative processes are not well-defined. The amyloid fibrils in the brains of Alzheimer's and prion disease patients are known to result in the inflammatory activation of certain cells. For example, primary microglial cultures and the THP-1 monocytic cell line are stimulated by fibrillar &bgr;-amyloid and prion peptides to activate identical tyrosine kinase-dependent inflammatory signal transduction cascades. The signaling response elicited by &bgr;-amyloid and prion fibrils leads to the production of neurotoxic products, which are in part responsible for the neurodegenerative. C. K. Combs et al,
J Neurosci
19:928-39 (1999).
In view of the above points, there is clearly a need for a method of clearing and/or preventing the formation of insoluble protein deposits associated with diseases such as Alzheimer's disease and prion-mediated disorders. Such a method would be effective in the treatment, prevention, and perhaps reversal of the neurological decline found in patients suffering from such disorders.
SUMMARY OF THE INVENTION
The present invention provides methods of arresting, preventing and/or reversing the impairment of physiologic systems, the methods comprising reducing the burden of insoluble protein deposits by the administration of branched polycationic agents or pharmaceutical compositions containing such branched polycationic agents. The agents used in the preferred method of the invention are highly-branched polycations, e.g. dendritic polycations.
In one embodiment, the invention provides pharmaceutical compositions for the tr

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