Case Number 097005 - Item Number 272 - Replication-Competent Herpes Simplex Viruses
Contact: Kellen Sensor
Description: The present invention relates to recombinant virus strains capable of killing tumor cells. More specifically, the present invention relates to a mutated, replication-competent virus which contains mutations in two genes, is hypersensitive to antiviral agents such as ganciclovir, is not neurovirulent and does not replicate in non-dividing cells, yet can kill nervous system tumor cells.
Malignant tumors of the nervous system are generally fatal, despite many recent advances in neurosurgical techniques, chemotherapy and radiotherapy. In particular, there is no standard therapeutic modality that has substantially changed the prognosis for patients diagnosed with malignant brain tumors. For example, high mortality rates persist in malignant medulloblastomas, malignant meningiomas and neurofibrosarcomas, as well as in malignant gliomas.
The present invention provides mutant, replication-competent HSV-1 viruses that can enter a tumor cell in situ, make multiple copies, lyse the tumor cell and spread to additional tumor cells with relatively minor effects on the surrounding normal cells.
The mutant herpes simplex virus of the present invention has each of the following characteristics: (1) efficacy in killing human brain tumor cells, (2) marked attenuation of generalized neurovirulence to protect the normal brain, (3) multiple deletions so that a single mutation cannot cause reversion to the wild-type viral phenotype, and (4) hypersensitivity to an antiviral agent so that undesired spread of the virus can be prevented. The mutant virus of the present invention is capable of replicating in neoplastic cells, and lysing the neoplastic cells, but spares surrounding non-neoplastic tissue.
The present invention provides a novel, alternative approach to eliminating the activity of a virally encoded, DNA metabolism enzyme, by direct mutations to those viral functions involved in the editing of the viral DNA. Because the HSV-1 genome is composed of 75% guanosine and cytosine nucleotides, the uracil DNA glycosylase function is especially important for efficient viral progeny production. The UNG activity corrects misincorporated uracil events and, potentially more importantly for HSV-1, the UNG activity removes uracils that arise by the spontaneous deamination of cytosine residues. Because non-dividing cells like neurons have insufficient levels of UNG activity, HSV-1 strains that replicate efficiently in neurons must encode their own. HSV-1 UNG- mutants are therefore reduced in their ability to cause neurovirulence.
Patent US 6,509,020