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Therapeutic Potential of NF-κB Inhibition in Glioblastoma: Gene Therapy Approach with rAAV-5 Mediated IκBαM
Ceera Manikandan1,2, Amit Kumar Jaiswal3
1School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632014, India.
Abstract:
Current treatment strategies for glioblastoma, including resection followed by concurrent chemotherapy/radiotherapy are not curative. Angiogenesis and hypoxia are two major factors responsible for GBM growth and resistance to existing therapies, leading to poor clinical outcomes. The transcription factor NF-κB induces tumour progression by activating genes associated with cell proliferation and angiogenesis. It is expressed constitutively in gliomas and is known to regulate the expression of HIF-1α and VEGF in GBM. As a result, NF-κB can be a potent target that can inhibit tumour growth/invasiveness by reducing hypoxia and angiogenesis, as well as preventing macrophage and microglia infiltration and generating inflammatory cytokines that cause gliomagenesis. AAV vectors are the typical transducing agents for gene therapy because they can infect a broad range of dividing and non-dividing cell types. AAVs have emerged as one of the most widely used methods for delivering genes into the central nervous system because of their broad range of infectivity, ability to induce long-term transgenic expression, and lack of toxicity. The present study aims to inhibit NF-κB activity by blocking its nuclear translocation via overexpression of IκBα utilising recombinant adeno-associated virus-5 plasmid as a gene therapy vector.
Insights
This study explores gene therapy to treat glioblastoma (GBM) by targeting the NF-κB pathway. Overexpressing IκBα using adeno-associated virus vectors aims to inhibit tumor growth and improve outcomes.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Gene Therapy
Background:
- Glioblastoma (GBM) treatments remain largely ineffective, with angiogenesis and hypoxia driving tumor progression and therapy resistance.
- The transcription factor Nuclear Factor-kappa B (NF-κB) promotes GBM growth by activating genes involved in proliferation and angiogenesis, and regulates Hypoxia-Inducible Factor 1-alpha (HIF-1α) and Vascular Endothelial Growth Factor (VEGF).
Purpose of the Study:
- To investigate the potential of inhibiting NF-κB activity as a therapeutic strategy for glioblastoma.
- To reduce tumor-induced hypoxia and angiogenesis by targeting NF-κB signaling.
Main Methods:
- Utilizing recombinant adeno-associated virus-5 (AAV-5) plasmid as a gene therapy vector.
- Overexpressing the inhibitor of NF-κB, IκBα, to block NF-κB nuclear translocation.
- Employing AAV vectors for gene delivery into the central nervous system due to their infectivity and safety profile.
Main Results:
- The study aims to demonstrate that inhibiting NF-κB can decrease tumor invasiveness.
- Reduced expression of genes associated with hypoxia and angiogenesis is anticipated.
- Prevention of inflammatory cytokine generation and reduced infiltration of macrophages and microglia are expected outcomes.
Conclusions:
- Targeting NF-κB via IκBα overexpression using AAV-5 vectors presents a promising gene therapy approach for glioblastoma.
- This strategy holds potential for inhibiting tumor growth, reducing invasiveness, and overcoming therapeutic resistance in GBM.
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