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Gene transfer to glial tumors using herpes simplex virus
Ajay Niranjan1, Darren Wolfe, Wendy Fellows
1Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Abstract:
Glial tumors occur as intraaxial masses in the brain and are uniformly fatal due to lack of effective therapy. Resection combined with radiation and chemotherapy fails to eradicate malignant cells infiltrating into normal brain, and recurrence at the original site is ultimately fatal. Gene transfer offers the potential to enhance tumor cell killing while sparing surrounding normal brain. Several approaches have been developed to deliver genes to tumor cells in order to kill these cells. The first strategy involves the use of viral vectors that are replication-competent, but depend on attributes unique to the tumor cell to support viral growth. Both replication-competent adenovirus and herpes simplex virus (HSV) vectors have been employed in pre-clinical studies and most recently in human clinical trials. For this purpose, HSV vectors have been engineered that replicate in dividing cells, such as tumor cells, but not in normal neurons. The use of conditional replication competent viruses could allow for their spread in tumor tissue while minimizing damage to normal brain, thus increasing the specificity and effectiveness. Such mutants include those lacking the viral thymidine kinase (tk) gene (4-7), ribonucleotide reductase gene (8,9), a protein kinase gene, or a gene (gamma34.5) required for growth specifically in neurons (11-13).
Insights
Gene therapy using replication-competent viruses shows promise for treating fatal glial tumors. Engineered herpes simplex virus (HSV) vectors selectively target and kill tumor cells, sparing healthy brain tissue.
Area of Science:
- Neuro-oncology
- Gene Therapy
- Virology
Background:
- Glial tumors are aggressive brain cancers with poor prognoses due to limited treatment efficacy.
- Current therapies like surgery, radiation, and chemotherapy struggle to eliminate infiltrating malignant cells, leading to inevitable recurrence.
Purpose of the Study:
- To explore gene transfer strategies for selectively killing glial tumor cells.
- To investigate the potential of replication-competent viral vectors for enhanced tumor cell eradication.
Main Methods:
- Utilizing replication-competent viral vectors, including adenovirus and herpes simplex virus (HSV).
- Engineering HSV vectors for conditional replication in dividing tumor cells but not in non-dividing neurons.
- Developing viral mutants deficient in genes like thymidine kinase (tk) or gamma34.5 for tumor-specific replication.
Main Results:
- Demonstrated pre-clinical and clinical application of viral vectors for glioblastoma treatment.
- Engineered HSV vectors exhibit tumor-selective replication, enhancing therapeutic specificity.
- Conditional replication-competent viruses show potential for tumor spread with minimized normal brain damage.
Conclusions:
- Gene therapy with engineered viral vectors offers a promising approach to target and eliminate glial tumors.
- Conditional replication-competent viruses, particularly HSV mutants, enhance treatment specificity and effectiveness.
- This strategy holds potential for improving outcomes in patients with currently fatal brain cancers.
