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Composition and method for treating cancer using herpes virus

a technology of herpes simplex and chemotherapy, applied in the field of chemotherapy with herpes simplex virus, can solve the problems of unfavorable universal use of vaccines for herpes viruses, inability to fully explain the relationship between the role of hsv-specific virus genes and immune reactions, and the inability to fully understand the relationship between the role of hsv-specific virus genes and the severity of herpes virus infection.

Inactive Publication Date: 2008-03-20
MS SCI CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this attenuated live virus was accidentally obtained and is based on the characteristic that chickenpox is more effective to humoral immunity since it causes systemic infection due to viremia, unlike other herpes viruses.
Therefore, a vaccine which can be universally utilized for herpes viruses is not yet available.
In this case, HSV infection causes serious symptoms.
For example, keratitis due to recurrent HSV is considered to be a major cause of blindness.
However, in the pathology of HSV diseases, a detailed relationship between the role of a HSV-specific virus gene and immune reactions has not been fully clarified.
Thus, under the present circumstances, there is no decisive method for preventing or treating diseases or disorders caused by herpes viruses.
However, none of these therapies have a sufficient effect on some types of cancers.
Particularly, when progressive pancreatic cancer or progressive ovarian cancer is disseminated to peritonea, prognosis after surgical excision is likely to fall short of expectations.
Since herpes simplex virus is a pathogenic virus, wild-type HSV cannot be used for cancer therapy.
However, the γ34.5-deficient strain has not yet become practical.

Method used

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  • Composition and method for treating cancer using herpes virus
  • Composition and method for treating cancer using herpes virus
  • Composition and method for treating cancer using herpes virus

Examples

Experimental program
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Effect test

example 1

Preparation of Attenuated HSV (UL39-Inactivated HSV)

[0304] A DNA fragment of HSV-1 containing the UL39 gene was incorporated into plasmid pBluescript (manufactured by Stratagene) for cloning, so as to prepare DNA having a lacZ cassette interrupting the open reading frame of the UL39 gene. In this case, the lacZ cassette is a DNA fragment containing a promoter for the HSV UL39 at the 5′ end thereof and the lacZ gene of E. coli and the polyadenylation signal of SV40 downstream of the promoter. Infectious HSV DNA was prepared from cells infected with HSV. Cells were transfected with this DNA. After three days, the produced viruses were collected. A plaque which was stained blue in the presence of X-gal was collected. Further plaque cloning was conducted three times. The resultant viruses were multiplied in Vero cells and then stocked. The thus obtained mutant was subjected to Southern blot, PCR, Western blot, and the like, so that it was confirmed that UL39 was inactivated.

example 2

Preparation of Attenuated HSV (Hh) in which UL39 and UL56 Genes not Involved in DNA and Deoxyribonucleotide Metabolism are Inactivated

[0305] There is provided a strain HF derived from HSV-1 in which a region containing the UL56 gene is deficient (kindly provided by Dr. Shin Isomura, Department of Pediatrics, Nagoya University School of Medicine). The pathogenicity of this strain is significantly low when inoculated intraperitoneally in a mouse as compared to a wild type of the strain. Further, the strain causes cell fusion with infected cells. Vero cells were infected with the above-described UL39-deficient virus and the strain HF. Among the progeny viruses, viruses which cause cell fusion and produce blue plaque in the presence of X-gal were collected. After cloning the viruses, it was confirmed by PCR and Western blot that UL39 and UL56 are deficient in the viruses.

example 3

Preparation of Strain in which Carboxyesterase is Incorporated into UL39-Inactivated HSV

[0306] A human carboxyesterase gene having a promoter for the immediate early gene of human cytomegalovirus was inserted to a lacZ gene (open reading frame) so that DNA in which the lacZ gene was interrupted by the human carboxyesterase gene was prepared. Vero cells were transfected with this DNA and infectious DNA derived from UL39-inactivated virus which has lacZ. Produced viruses were collected. Viruses which produced colorless plaques in the presence of X-gal were collected, followed by plaque cloning. The resultant viruses were stored as a primary stock. Cell samples were infected with clones obtained as the primary stock. The cell samples were subjected to a fluorescent antibody technique using tagged antibodies. For positive clones, a secondary stock was prepared. The finally obtained clones were confirmed to induce carboxyesterase activity in infected cells.

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Abstract

The present invention provides a herpes virus in which a non-essential gene for replication is inactivated. More particularly, the present invention provides a herpes virus in which a non-essential gene for replication present in a UL or US region is inactivated. More preferably, the non-essential gene for replication contains US3 or UL56. The herpes virus may be preferably a herpes simplex virus, and more preferably herpes simplex virus 1 or herpes simplex virus 2. The present invention provides a method, composition and use for treating various diseases or disorders including tumor and infectious diseases. The present invention also provides a method, composition and use for activating a prodrug.

Description

TECHNICAL FIELD [0001] The present invention relates to a novel herpes simplex virus (hereinafter may be herein abbreviated as HSV) construct. More specifically, the present invention relates to a method, use and a composition for treatment, therapy, or prevention of various diseases or disorders (e.g., cancer, bacterial infectious diseases, viral infectious diseases, and the like) using a novel herpes virus construct. BACKGROUND ART [0002] The first record of herpes virus in history dates back to the ancient Greece era before Christ. Herpes virus infrequently develops after primary infection, but hides in ganglia or the like for along time. When the immune ability of a human is reduced, the virus is activated and proliferates to develop symptoms. In this case, herpes virus targets a wide range of tissues, such as skin, genital organs, eye ball, nerves, and the like. Even though antibodies which neutralize the virus are present in blood, symptoms often appear. It is thus believed th...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/00A61K35/00C12N15/09A61K31/337A61K31/4375A61K31/522A61K35/76A61K39/245A61P31/04A61P31/14A61P31/16A61P31/18A61P31/22A61P35/00A61P43/00C12N7/04C12N15/869
CPCA61K2039/541C12N7/00A61K31/522A61K31/4745A61K31/337C12N2710/16062C12N2710/16032A61K35/763C12N2710/16651C12N15/86C12N2710/16632C12N2710/16643A61K2300/00A61P31/04A61P31/12A61P31/14A61P31/16A61P31/18A61P31/22A61P35/00A61P43/00
Inventor NISHIYAMA, YUKIHIRO
Owner MS SCI CORP
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