Replication-competent herpes simplex virus mediates destruction of neoplastic cells

• US 8,273,568 B2
• Filed: 03/01/2004
• Issued: 09/25/2012
• Est. Priority Date: 06/23/1994
• Status: Expired due to Fees

• Current Assignee: Georgetown University
• Original Assignee: Georgetown University
• Inventors: Martuza, Robert L., Rabkin, Samuel D., Mineta, Toshihiro
• Primary Examiner(s): SHEN, WU CHENG WINSTON
• Application Number:
  US10/788,410
• Publication Number:
  US 20040228841A1
• Time in Patent Office: 3,130 Days
• Field of Search: 435/320.1, 536/23.1
• US Class Current: 435/320.1
• CPC Class Codes: A01K 2217/05 Animals comprising random inserted nucleic acids (transgenic)
• CPC Class Codes: A01K 2267/0331 Animal model for proliferative diseases
• CPC Class Codes: A01K 67/0271 Chimeric vertebrates, e.g. comprising exogenous cells
• CPC Class Codes: A61K 2039/525 Virus
• CPC Class Codes: A61K 2121/00 Preparations for use in therapy
• CPC Class Codes: A61K 35/763 Herpes virus
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: C07K 14/005 from viruses
• CPC Class Codes: C12N 15/8509 for producing genetically modified animals, e.g. transgenic
• CPC Class Codes: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 2710/16622 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12N 2710/16632 Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
• CPC Class Codes: C12N 2710/16643 viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2830/00 Vector systems having a special element relevant for transcription
• CPC Class Codes: C12N 7/00 Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00

Abstract

A method for killing malignant brain tumor cells in vivo entails providing replication competent herpes simplex virus vectors to tumor cells. A replication competent herpes simplex virus vector, with defective expression of the γ34.5 gene and the ribonucleotide reductase gene, specifically destroys tumor cells, is hypersensitive to anti-viral agents, and yet is not neurovirulent.

Claims

1. A herpes simplex virus with a genome that comprises (i) an expressible non-herpes simplex virus nucleotide sequence encoding a cytokine capable of eliciting an immune response against a tumor cell, and (ii) an alteration in the γ

34.5 gene such that no functional γ

34.5 gene product is made, wherein the neurovirulence of said herpes simplex virus is attenuated.

2. The herpes simplex virus of claim 1, further comprising at least one further gene alteration.

3. The herpes simplex virus of claim 2, wherein said at least one further gene alteration is in the ribonucleotide reductase gene, such that no functional ribonucleotide reductase is made.

4. The herpes simplex virus of claim 3, wherein said herpes simplex virus is G207 expressing the cytokine.

5. The herpes simplex virus of claim 1, wherein an essential viral gene product of said virus is under the control of a tumor cell-specific promoter rather than its own viral promoter.

6. A composition comprising the herpes simplex virus of claim 1 and a pharmaceutically acceptable vehicle for said virus.

7. The herpes simplex virus of claim 5, wherein said tumor cell-specific promoter is nestin promoter.

8. The herpes simplex virus of claim 5, wherein said tumor cell-specific promoter is basic fibroblast growth factor promoter.

9. The herpes simplex virus of claim 5, wherein said tumor cell-specific promoter is epidermal growth factor promoter.