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The application of genetically engineered herpes simplex viruses to the treatment of experimental brain tumors
S S Andreansky1, B He, G Y Gillespie
1Department of Pediatrics, University of Alabama at Birmingham 35233, USA.
Abstract:
Due to lack of effective therapy, primary brain tumors are the focus of intense investigation of novel experimental approaches that use vectors and recombinant viruses. Therapeutic approaches have been both indirect, whereby vectors are used, or direct to allow for direct cell killing by the introduced virus. Genetically engineered herpes simplex viruses are currently being evaluated as an experimental approach to eradicate malignant human gliomas. Initial studies with gamma (1)34.5 mutants, R3616 (from which both copies of the gamma (1)34.5 gene have been deleted) and R4009 (a construct with two stop codons inserted into the gamma (1)34.5 gene), have been assessed. In a syngeneic scid mouse intracranial tumor model, recombinant herpes simplex virus can be experimentally used for the treatment of brain tumors. These viruses and additional engineered viruses were subsequently tested in human glioma cells both in vitro and in vivo. Using a xenogeneic scid mouse intracranial glioma model, R4009 therapy of established tumors significantly prolonged survival. Most importantly, long-term survival was achieved, with histologic evidence that R4009 eradicated intracranial tumors in this model. Furthermore, the opportunity to evaluate gamma (1)34.5 mutants that have enhanced oncolytic activity, e.g., R8309 where the carboxyl terminus of the gamma (1)34.5 gene has been replaced by the murine homologue, MyD116, are considered.
Insights
Genetically engineered herpes simplex viruses show promise for treating brain tumors. A specific mutant virus, R4009, eradicated intracranial tumors in mice, offering hope for effective glioma therapy.
Area of Science:
- Oncolytic virology
- Neuro-oncology
- Gene therapy
Background:
- Primary brain tumors lack effective therapies, driving research into novel treatments.
- Recombinant viruses and vectors are being explored for direct cell killing or indirect therapeutic effects.
Purpose of the Study:
- To evaluate genetically engineered herpes simplex viruses, specifically gamma (1)34.5 mutants, as a potential therapy for malignant gliomas.
- To assess the efficacy of R4009, a gamma (1)34.5 mutant, in eradicating established intracranial tumors.
Main Methods:
- Testing of gamma (1)34.5 deleted (R3616) and stop codon (R4009) mutants in syngeneic and xenogeneic scid mouse intracranial tumor models.
- In vitro and in vivo evaluation of recombinant herpes simplex viruses in human glioma cells.
Main Results:
- Recombinant herpes simplex viruses demonstrated experimental utility in treating brain tumors in mouse models.
- R4009 therapy significantly prolonged survival in a xenogeneic scid mouse glioma model with established tumors.
- Histologic evidence confirmed R4009 eradication of intracranial tumors, leading to long-term survival.
Conclusions:
- Genetically engineered herpes simplex virus R4009 shows significant oncolytic activity against intracranial gliomas.
- This study provides evidence for the potential of R4009 as a therapeutic agent for malignant gliomas.
- Further investigation into enhanced gamma (1)34.5 mutants, like R8309, is warranted for improved oncolytic efficacy.