Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1997-08-14
2001-09-18
Clark, Deborah J. R. (Department: 1633)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S04400A, C434S199000, C434S204000, C434S230000, C434S233000, C435S320100, C435S325000
Reexamination Certificate
active
06291437
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to pharmaceutical compositions and methods of use thereof in treating or preventing atherosclerosis.
BACKGROUND OF THE INVENTION
Atherosclerosis (AT) results from an excessive inflammatory and fibroproliferative response to vascular insult and has been noted to be a principal cause of heart attack and stroke, accounting for up to half of all mortalities in the industrialized world including about 13 million Americans. Atherogenesis is theorized to follow a response to injury, but the agent(s) of injury have yet to be identified fully.
Viral and/or bacterial infection(s) have been found to be associated in some way with the complex process of the development of AT. Particles, antigens and DNA sequences of human cytomegalovirus (HCMV), a member of the herpesvirus group, have been described in AT plaques of biopsy or autopsy material [M. G. Hendrix et al,
Am. J. Pathol
., 136:23-28 (1990); J. L. Melnick et al.,
BioEssays
, 17(10): 899 (October 1995)]. However, Melnick, cited above, states that the “observations do not demonstrate a viral role in the pathogenesis of atherosclerosis”. The possible involvement of reactivated HCMV in restenosis of coronary arteries, an accelerated form of AT, following angioplastic surgery has been suggested [S. E. Epstein et al,
Lancet
, 348:13-17 (1996); E. Speir et al,
Science
, 265:391-394 (1994); Y. F. Zhou et al,
N. Engl. J. Med
., 335: 624-630 (1996)]. Seroepidemiologic data show that HCMV infection usually occurs in childhood, paralleling the pattern of the appearance of early AT lesions; by young adulthood, 50-100% of individuals are HCMV-seropositive. In some individuals, the virus is apparently reactivated in artery walls, where it may initiate abnormal cell growth that can lead to blocked blood flow and, ultimately, heart attack.
The bacterium
Chlamydia pneumoniae
is an intracellular bacterium, which has been established as an important pathogen in acute and chronic respiratory infections [J. T. Grayson,
Clin. Infect. Dis
., 15:757-763 (1992)] has also been associated with AT [J. A. Ramirez,
Ann. Intern. Med
., 125:979-982 (1996)]. This bacterium infects about 50% of the population and causes flu-like diseases, but also replicates in the arterial wall.
C. pneumoniae
antigens and DNA have been detected in human AT plaques. Population antibody prevalence studies have shown that more than 50% of adults worldwide have antibody. While antibody is infrequent in children under age 5 years, incidence studies have demonstrated antibody conversion of 6-9% per year in children from the ages 5-14 years. The prevalence of antibody continues to increase throughout adulthood, and is highest in the elderly.
Recently,
C. pneumoniae
, strain TWAR, has been associated with AT based on both seroepidemiology and data demonstrating the presence of the organism in AT plaques. For example, serologic studies from Finland, the United States and other countries have shown that patients with coronary artery diseases were significantly more likely to have serologic evidence of past infection with TWAR than were controls. Morphologic and microbiological evidence of the persistence of TWAR in atheromatous plaques has been obtained by electron microscopic studies, immunochemical staining and PCR testing of coronary, carotid and aortic atheroma [C.-C. Kuo et al,
Clin. Microbiol. Rev
., 8:451-461 (1995)]. In addition,
C. pneumoniae
activates growth factors involved in inflammatory responses and changes lipoprotein metabolism of infected cells. Immune responses to chlamydial infections are partly protective but also deleterious, and delayed hypersensitivity (DH) is thought to play a pathogenic role in chlamydial disease [R. P. Morrison et al,
J. Exp Med
., 170:1271-1283 (1989)].
Despite the wealth of reports, no etiological role of HCMV and/or
C. pneumoniae
in the development of AT has been established. Thus, there remains a need in the art for reagents and methods useful in ameliorating the symptoms and development of atherosclerosis in response to these microorganisms.
SUMMARY OF THE INVENTION
In one aspect, the invention provides a method for the treatment or prophylaxis of atherosclerosis in a mammal, preferably a human, comprising administering to a mammal an effective amount of a composition comprising a human cytomegalovirus (HCMV) protein or fragment thereof, the amount capable of inducing cell mediated immunity and anti-CMV antibody response in the mammal. The composition preferably may be administered to infants or immunocompromised patients.
In another aspect the invention provides a method for the treatment or prophylaxis of atherosclerosis in a mammal comprising administering to a mammal an effective amount of a composition comprising a nucleic acid sequence encoding a human cytomegalovirus (HCMV) protein or fragment thereof, said composition capable of inducing cell mediated immunity (CMI) and inducing an anti-CMV antibody response upon expression of said protein in the mammal.
In still another aspect, the invention provides a method for the treatment or prophylaxis of atherosclerosis in a mammal, preferably a human, comprising administering to a mammal an effective amount of a composition comprising a
Chlamydia pneumoniae
protein or fragment thereof, the amount capable of inducing cell mediated immunity and anti-
C. pneumoniae
antibody response in the mammal. The composition preferably may be administered to infants or immunocompromised patients.
In yet another aspect the invention provides a method for the treatment or prophylaxis of atherosclerosis in a mammal comprising administering to a mammal an effective amount of a composition comprising a nucleic acid sequence encoding a
C. pneumoniae
protein or fragment thereof, said composition capable of inducing cell mediated immunity (CMI) and inducing an anti-
C. pneumoniae
antibody response upon expression of said protein in the mammal.
In another aspect, the invention provides a therapeutic or prophylactic composition comprising a
Chlamydia pneumoniae
protein or fragment thereof and an HCMV protein or fragment thereof in a pharmaceutically acceptable carrier.
In still another aspect, the invention provides a therapeutic or prophylactic composition comprising an anti-microbial agent effective against
Chlamydia pneumoniae
infection and an HCMV protein or fragment thereof in a pharmaceutically acceptable carrier.
In yet another aspect, the invention provides a method for treating atherosclerosis or restenosis by administering to a mammal having physical evidence of atherosclerosis or restenosis an effective amount of an anti-microbial agent directed against
Chlamydia pneumoniae
infection.
In a further aspect, the invention provides a method for preventing restenosis after coronary atherectomy or balloon angioplasty comprising treating a patient prior to, or after said atherectomy or angioplasty with an effective amount of said
C. pneumoniae
/HCMV composition described above or with an effective amount of an anti-microbial agent directed against
Chlamydia pneumoniae
infection.
Other aspects and advantages of the present invention are described further in the following detailed description of the preferred embodiments thereof.
REFERENCES:
patent: 5424187 (1995-06-01), Shor
patent: 5534258 (1996-07-01), Golubev
patent: 5552143 (1996-09-01), Plotkin et al.
patent: 5591439 (1997-01-01), Plotkin et al.
patent: WO97/40165 (1997-10-01), None
patent: WO98/33510 (1998-08-01), None
Melnick et al, BioEssays 17(10):899-903 1995.*
Kuo et al, Proc. Natl. Acad.Sci. USA 92:6911-6914 1995.*
Commentry, Science, 265:320, 1994.*
Melnick et al, J Med. Virol. 42:170-174, 1994.*
Speir et al, Science 265:391-393, 1994.*
Gonczol et al, Vaccine 13(12):1080-1085, 1995.*
Gonczol et al Vaccine 13(12):1080-1085, 1995.*
Endresz et al, Vaccine 17:50-58, 1999.*
Commentary, Science, 265:320, 1994.*
Melnick et al, BioEssays 17(10):899-903, 1995.*
J. Melnick et al, “Possible Role of Cytomega
Berencsi Klara
Gonczol Eva
Clark Deborah J. R.
Howson and Howson
Kaushal Sumesh
The Wistar Institute of Anatomy and Biology
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