Gene Therapy Strategies for Malignant Gliomas

Malignant gliomas, particularly glioblastoma, remain among the most lethal central nervous system tumours, characterised by diffuse infiltration, molecular heterogeneity and resistance to conventional therapies. Gene therapy seeks to exploit molecular vulnerabilities by delivering therapeutic genes directly into tumour cells or into their microenvironment. Strategies include suicide gene therapy, wherein enzymes such as thymidine kinase or cytosine deaminase convert non-toxic prodrugs into cytotoxic metabolites; oncolytic virotherapy, which employs replication-competent viruses engineered to lyse tumour cells and stimulate antitumour immunity; and immunomodulatory approaches, whereby genes encoding cytokines or chimeric antigen receptors enhance host immune recognition. Delivery vehicles range from viral vectors (adenovirus, retrovirus, lentivirus, adeno-associated virus) to non-viral systems (lipid or polymer nanoparticles, exosomes) and cell-based carriers such as mesenchymal stem cells. Recent innovations include regulatable gene switches to control transgene expression, blood–brain barrier-penetrant nanoparticles, and combination regimens integrating gene therapy with radiotherapy, chemotherapy or immune checkpoint inhibitors. Despite formidable challenges—delivery efficiency across the blood–brain barrier, intratumoral spread, off-target effects and immunosuppression—preclinical and early clinical studies demonstrate safety and hints of efficacy. Continued refinement of vector design, targeting specificity and multimodal regimens holds promise for transforming the management of malignant gliomas.

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Gene Therapy Strategies for Malignant Gliomas publication trend

The graph below shows the total number of articles in gene therapy strategies for malignant gliomas across all publications each year (not limited to Nature Index journals).

Technical terms

Suicide gene therapy: Introduction of a gene encoding an enzyme that converts an inactive prodrug into a cytotoxic agent within tumour cells.

Oncolytic virus: A genetically modified virus that selectively infects, replicates within and lyses cancer cells while sparing normal tissue.

Viral vector: A virus-based delivery vehicle engineered to carry and express therapeutic genes in target cells.

Non-viral vector: A synthetic delivery system, such as lipid or polymer nanoparticles, used to transport genetic material into cells.

Blood–brain barrier: A specialised endothelial interface that restricts the passage of substances from the circulation into the central nervous system.

Prodrug: An inactive compound that is metabolised in the body—often by a therapeutic enzyme—into its active, cytotoxic form.

References

1. Suicide gene therapy using allogeneic adipose tissue-derived mesenchymal stem cell gene delivery vehicles in recurrent glioblastoma multiforme: a first-in-human, dose-escalation, phase I clinical trial. Journal of Translational Medicine (2023).
2. Current Approaches for Glioma Gene Therapy and Virotherapy. Frontiers in Molecular Neuroscience (2021).
3. Suicide gene therapy for the treatment of high-grade glioma: past lessons, present trends, and future prospects. Neuro-Oncology Advances (2020).
4. Regulated intratumoral expression of IL-12 using a RheoSwitch Therapeutic System® (RTS®) gene switch as gene therapy for the treatment of glioma. Cancer Gene Therapy (2018).