Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Recombinant virus encoding one or more heterologous proteins...
Reexamination Certificate
1997-02-05
2001-02-06
Mosher, Mary E. (Department: 1641)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Recombinant virus encoding one or more heterologous proteins...
C424S199100, C424S230100, C424S277100, C424S093200, C435S320100, C514S04400A
Reexamination Certificate
active
06183752
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compositions and methods for the diagnosis, prophylaxis and/or therapy of restenosis and/or atherosclerosis.
The present invention relates to the use of an agent for decreasing viral load, e.g., an immunological composition, preferably a vaccine, against cytomegalovirus and/or p53 for therapy for restenosis and/or atherosclerosis; and, to a method for providing therapy for restenosis and/or atherosclerosis comprising administering the agent for decreasing viral load, e.g., an immunological composition or vaccine, against cytomegalovirus (CMV) and/or p53.
“Viral load” and “virus load”, as used herein, can have their art-recognized definitions, and can refer to active virus, e.g. virus in circulation or infectious, non-dormant virus, as well as virus which is latent or dormant awaiting reactivation or reactivating, or virus which is having an abortive replication cycle. While restenosing patients may not have any increase in IgG or IgM, Applicants, without wishing to necessarily be bound by any one particular theory, submit that viral reactivation following angioplasty/atherectomy can occur; and, that this viral reactivation, in some instances, may only proceed as far as the turn-on of IE genes and not up to viremia. Thus, “viral activation” is included in “viral load” and “virus load” herein. Further, “atherectomy” is included in “angioplasty” herein.
The CMV antigen can derive from any CMV protein, including immediate early (IE), early, or late gene products. The antigen can be the entire protein or an antigenic portion thereof.
The p53 can be wild-type or a mutant, e.g., full-length p53 or a truncated antigenic portion thereof.
The antigen(s) can be derived recombinantly, e.g., from expression by a virus, bacteria, or plasmid, in vitro, with subsequent isolation and purification; or from expression by a recombinant in vivo. Preferred expression systems include generally adenovirus, baculovirus, poxvirus, and DNA vector systems. For in vivo use, a recombinant adenovirus or poxvirus, such as a vaccinia virus or avipox virus (e.g., canarypox virus), or a DNA vector system are preferred; but, any suitable vector system, including naked DNA, may be employed. Indeed, as herpesvirus vectors are known, a replication-deficient herpesvirus vector, e.g., a replication-defective HSV or CMV vector could even be used in embodiments of the invention.
The invention thus relates to stimulating an immune response, preferably a cellular immune response, directed against CMV and/or p53 to inhibit or prevent restenosis and/or atherosclerosis and/or smooth muscle proliferation. Such a response can cause cell lysis and thus inhibition of smooth muscle cell proliferation and/or inhibition of atherosclerosis and/or restenosis. Thus, the invention relates to methods for inducing cell lysis of smooth muscle cells and/or inhibition of smooth muscle cell proliferation to treat or prevent restenosis and/or atherosclerosis.
The administration of the immunological composition or vaccine can be before or at the time of angioplasty, e.g., coronary and/or peripheral angioplasty, to prevent the development of restenosis, or independently of angioplasty, to provide treatment for atherosclerosis. It can also be administered any time during the lifetime of the individual, from childhood to adulthood, to prevent the development or progression of atherosclerosis. Thus, the invention relates to a therapeutic method for treatment of atherosclerosis and/or restenosis.
The immunological composition or vaccine can be administered alone or with additional therapeutic treatment; and, the invention further relates to additional methods for therapeutic treatment of restenosis and/or atherosclerosis.
The additional therapeutic treatment can comprise therapy for decreasing viral burden, e.g., the administration of: antioxidants which inhibit the replication of CMV and the cytopathic effect of viral infection, and/or compositions which reduce the transcriptional activity of CMV (transcriptional activity reducer) and/or compositions which decrease reactive oxygen species (ROS) generated by the arachidonic cascade and/or the xanthine/xanthine oxidase system (ROS reducer). Additionally or alternatively, the additional therapeutic treatment can comprise administration of an antiviral agent such as gancyclovir and/or acyclovir.
Thus, the invention still further relates to a method for treatment of atherosclerosis and/or restenosis comprising administering a sufficient dose or doses of at least one agent for decreasing viral burden and/or directed to interfering with SMC proliferation, e.g., antioxidant which inhibits the cytopathic effect of viral infection and/or transcriptional activity reducer and/or ROS reducer, either alone, or in conjunction with the aforementioned immunological composition or vaccine therapy.
The antioxidant can be one or more of Vitamin C, Vitamin E, NAC, PDTC, and the like.
The transcriptional activity reducer can be an antiviral drug such as gancyclovir and/or acyclovir (which interfere with viral replication), and/or an antioxidant, or the like.
The ROS reducer can be aspirin (acetylsalicylic acid) or a derivative thereof, ASA, Indomethacin, oxypurinol, and the like.
Accordingly, the invention additionally relates to a method for treating restenosis and/or atherosclerosis comprising, after angioplasty: administering a sufficient dose or doses of an immunological composition, preferably a vaccine, against CMV and/or p53; or administering a sufficient dose or doses of an immunological composition, preferably a vaccine, against CMV and/or p53, with or without a sufficient dose or doses of an antioxidant which inhibits viral infection and/or the cytopathic effect of viral infection and/or transcriptional activity reducer and/or ROS reducer; or administering a sufficient dose or doses of one or more antioxidant which inhibits viral replication and/or the cytopathic effect of viral infection and/or transcriptional activity reducer and/or ROS reducer.
The compositions administered after angioplasty can be used before angioplasty, to prevent, i.e., as a prophylaxis against, restenosis and/or atherosclerosis.
Accordingly, the invention relates to a method for preventing restenosis and/or atherosclerosis comprising, before angioplasty: administering a sufficient dose or doses of an immunological composition, preferably a vaccine, against CMV and/or p53; or administering a sufficient dose or doses of an immunological composition, preferably a vaccine, against CMV and/or p53 with or without a sufficient dose or doses of at least one composition for decreasing viral burden and/or directed to interfering with SMC proliferation, e.g., antioxidant which inhibits the cytopathic effect of viral infection and/or transcriptional activity reducer and/or ROS reducer; or administering a sufficient dose or doses of at least one agent for decreasing viral burden and/or directed to interfering with SMC proliferation, e.g., antioxidant which inhibits the cytopathic effect of viral infection and/or transcriptional activity reducer and/or ROS reducer. Thus, the invention can relate to treatment or prophylaxis directed at both decreasing viral loads, and decreasing SMC proliferation.
Interesting therapeutic or prophylactic compositions and methods of the invention relate to recombinants, especially for in vivo use, expressing a CMV antigen or portion thereof, or p53 or a portion thereof, or a combination of a CMV antigen or portion thereof and p53 or a portion thereof. These recombinants can additionally express or be used in conjunction with another form of molecular based therapy, e.g., expression of cytotoxic molecules to inhibit proliferation of smooth muscle cells, gene therapy, or antisense strategies to inhibit expression of gene products for cell proliferation. Thus, an embodiment can be providing treatment directed at decreasing viral load and treatment directed at reducing SMC proliferation.
Accordingly in certain aspects, the present invention relates to vaccine or im
Epstein Stephen E.
Erdile Lorne
Finkel Toren
Pincus Steven
Speir Edith
Frommer William S.
Frommer & Lawrence & Haug LLP
Kowalski Thomas J.
Mosher Mary E.
Pasteur Merieux Serums et Vaccins
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