Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1995-06-07
2004-04-27
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S275000, C514S457000, C514S449000, C514S450000, C514S724000, C514S406000, C514S407000, C514S266400
Reexamination Certificate
active
06727278
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to the identification of compounds that act, at physiologically-compatible levels, to inhibit the formation of proteinaceous tissue deposits denoted generically as “amyloid.” More specifically, the present invention relates to pharmaceutically active agents that impede formation of amyloid fibrils in vivo, and to a method for the screening of compounds which possess this activity.
Classified under the rubric “amyloidosis” are a number of pathological conditions characterized by the deposition of abnormal fibrils (“amyloid fibrils”) in extracellular spaces. The amyloid fibril, in turn, represents a final common pathway for a diverse array of proteins. Regardless of their biochemical composition, however, all types of amyloid fibrils share (a) a &bgr;-pleated sheet structure, (b) green birefringence under polarized light after staining with Congo Red dye, and (c) a fibrillar morphology which has a typical electron-microscopic appearance.
The deposition of amyloid fibrils can affect several organs in the systemic forms of the disorder, exemplified by familial Mediterranean fever, familial amyloid polyneuropathy and systemic amyloidosis, or it can be restricted to one organ in localized forms. Among the latter are conditions classified under the rubric “cerebral amyloidosis,” which covers the Alzheimer group of diseases, namely, Alzheimer's disease [pre-senile dementia, senile dementia]; Alzheimer's disease associated with Down's syndrome; Alzheimer's disease associated with other central-nervous-system diseases, such as Parkinson's disorder; and congophilic angiopathy [associated or not associated with Alzheimer's disease]
There is no effective therapy for cerebral amyloidosis, which almost invariably has a fatal outcome following the onset of amyloid deposits. For example, Alzheimer's disease is estimated to be the fourth or fifth leading cause of death among North Americans.
A universally accepted indicator of cerebral amyloidosis is the accumulation of large numbers of lesions, so-called “senile plaques,” that are comprised in large part of amyloid fibrils. Senile plaques are spherical, ranging from 10 to 200 &mgr;m in diameter, and are found occasionally in aged adult cerebral cortex but in large numbers in Alzheimer-affected cortex.
The utilizing of materials found in human brain (normal or Alzheimer-affected) that are not already amyloid, and of transforming them into amyloid, has not been documented in the literature. There was also no description in the art of an experimental system, derived exclusively from human materials, that was characterized by the feature of Alzheimer's disease. Because the presence of amyloid is the most qualitatively and quantitatively specific indication of senile-plaque formation, most specialists agree that reproduction of amyloid fibrils experimentally from precursor materials which are extracted, activated, or otherwise derived from human brain would constitute the best available evidence linking an agent or precursor to the progression of cerebral amyloidosis.
Despite the recognized importance of an experimental system that would permit testing for such a linkage, it has not been possible to reproduce amyloid experimentally from materials derived solely from human brain tissue. Accordingly, there has been no reliable indicator available for compounds that might be effective in treating cerebral amyloidosis; nor has it been possible to determine whether a group of compounds exists that block the conversion of a brain-localized precursor to cerebral amyloid (i.e., that display “anti-amyloid activity”) at physiologically acceptable levels of the active agent.
A microscopic structure referred to as the dense microsphere is known to exist in normal brain and in brain affected by Alzheimer's disease. See Averback,
Acta Neuropathol.
61: 148-52 (1983); results confirmed by Hara,
J. Neuropath. Exp. Neurol.
(1986). Evidence for the existence of dense microspheres (DMS) comes from microscopic histological section studies of fixed whole brain tissue, where the dense microspheres are seen to have a proteinaceous central region (“DMS protein”) surrounded by continuous membrane (“DMS membrane”). The dense microspheres are observed as randomly dispersed, very infrequent structures which occupy an estimated 10
−9
or less of total brain volume, at a unit frequency roughly estimated at 10
−16
or less, relative to other definable brain structures such as mitochondria.
Neither the extraction, purification and characterization of isolated samples of DMS nor the use of DMS material to any advantage has been documented. Thus, DMS are structures of unproven function and unknown significance or usefulness, and have been effectively unavailable in tangible form.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide a method for the screening of therapies for usefulness in impeding amyloid formation and, hence, in treating cerebral amyloidosis, that is characterized by the presence abnormal amounts of amyloid &bgr;-protein.
It is also an object of the present invention to provide a method of treating &bgr;-amyloid diseases by the administration of a compound selected from a class of pharmaceutically active agents that have in common an ability to inhibit, at physiologically-acceptable levels, the formation of amyloid fibrils in vivo.
It is yet another object of the present invention to provide antibodies that can be used to detect the presence of DMS in biological samples.
It is still another object of the present invention to provide a means for ascertaining whether a given individual is at risk of developing cerebral amyloidosis, even when the individual may not yet have developed clinical symptoms associated with the latter malady.
In accomplishing the foregoing objects, a method has been provided, in accordance with one aspect of the present invention, for treating cerebral amyloidosis, comprising the step of administering to a subject, in whom amyloid formation is anticipated, a pharmaceutically effective amount of a compound that inhibits formation of amyloid fibrils when administered, at an in-tissue concentration of about 10
−5
M or less, to a test animal that has received an intracerebral injection of DMS. In one preferred embodiment, the compound thus administered inhibits amyloid formation by acting on DMS components in such a way that a structural transition of DMS protein in situ to a &bgr;-pleated sheet conformation is prevented. The method can be employed where the subject does not display clinical or other evidence indicative of Alzheimer's disease or dementia associated with another disease state, as well as when symptoms of dementia are not evident but the subject tests positive for increased. risk of Alzheimer's disease or dementia due to another disease state. The method can also be administered to prevent a decline in brain function in the subject when the decline is short of dementia.
In accordance with another aspect of the present invention, there has been provided a composition of matter consisting essentially of antibodies, preferably monoclonal antibodies, that are reactive against dense microspheres derived from mammalian brain tissue.
A method has also been provided, in accordance with still another aspect of the present invention, for identifying individuals at risk of suffering cerebral amyloidosis, comprising the step of detecting the presence of a DMS component or an anti-DMS antibody in a biological sample of a mammalian subject, wherein the sample is not derived from brain tissue. In one preferred embodiment, the method comprises the steps of (a) providing antibodies that are reactive with a DNS component, (b) bringing the antibodies into contact with the biological sample and (c) determining whether the antibodies react with the sample. In another preferred embodiment, the method comprises (a) providing a composition comprised of a DMS componen
Criares Theodore J.
DMS Pharmaceutical Inc.
Foley & Lardner
LandOfFree
Pharmaceutically active agents that impede amyloid formation... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pharmaceutically active agents that impede amyloid formation..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pharmaceutically active agents that impede amyloid formation... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3196185