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INTERNATIONAL CONGRESS OF

CancerGenetics

• CRISPR-Based Restoration of TP53 Function in Glioblastoma: A Gene Editing Approach to Tumor Suppression

• Ali Rezaei,¹ Paria sadat Aghaseyedmirzaei,² Shirin Farivar,^3,*
  1. Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University
  2. Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University
  3. Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University
  
  
  
• Introduction: Glioblastoma (GBM) stands as the most aggressive primary brain tumor because patients survive for less than 15 months even when treated with surgery, radiotherapy, and chemotherapy. GBM tumors frequently develop TP53 mutations, which result in cell cycle control malfunction, apoptosis resistance, and faster tumor growth. The CRISPR/Cas9 system enables scientists to fix TP53 gene mutations and reactivate its functional pathways, which makes it a promising therapeutic approach. Recent genomic studies have shown the central role of TP53, which is often accompanied by alterations in PTEN and EGFR pathways. This review examines the application of CRISPR-based TP53 restoration for glioblastoma treatment.
• Methods: The analysis focused on experimental research conducted after 2020 which employed CRISPR/Cas9 and its derivatives to modify TP53 in glioblastoma models. The research team conducted specific database searches to find studies about TP53 restoration, CRISPR editing, and glioblastoma tumor suppression. The research focused on understanding mechanisms, preclinical model results, and the challenges in clinical application. Special attention was given to innovative gene-editing platforms such as base editors and prime editors.
• Results: 1. CRISPR-mediated TP53 restoration and reactivation Recent research show that CRISPR-based TP53 restoration in GBM cells leads to reduction in tumor expansion and enhanced apoptosis. CRISPR activation systems (CRISPRa) that target TP53-responsive promoters enhance TP53 transcriptional activity, which makes GBM cells more responsive to chemotherapy treatments. In xenograft models, TP53 editing restored apoptosis via caspase-3 activation and reduced proliferation markers such as Ki-67. This result showed the direct impact of TP53 on tumor cell kinetics. Furthermore, CRISPRa-induced reactivation of TP53 increased the expression of DNA damage sensors like GADD45 and ATM and strengthened the DNA repair checkpoint in GBM cells. 2. Synthetic lethality and combination therapies The restoration of TP53 function through CRISPR technology creates a synergistic effect when used with specific targeted treatments. The combination of restored TP53 function with DNA damage response pathway inhibitors leads to enhanced tumor cell death without harming normal cells. The treatment method tackles GBM's well-known resistance to therapy and its heterogeneity. For example, experiments combining TP53 correction with PARP inhibitors produced up to a 70% reduction in tumor volume in mouse orthotopic GBM models, whereas either therapy alone achieved only modest effects. Similarly, p53 reactivation enhanced radiosensitivity, which lowered the required radiation dose to achieve tumor control. 3. Precision delivery challenges Scientists continue to develop methods for delivering CRISPR through nanoparticles and viral vectors, which can penetrate the blood–brain barrier (BBB) to specifically target GBM cells. Research indicates that safe and efficient in vivo delivery methods face significant challenges, but lipid nanoparticles and adeno-associated virus (AAV) vectors show promise. Notably, engineered AAV-PHP.B variants demonstrated efficient CNS transduction in murine models, while polymer-coated lipid nanoparticles achieved selective uptake in glioma cells with minimal distribution to healthy neurons. These advances suggest that targeted delivery across the BBB is achievable, but scalability and immune responses remain unresolved challenges. 4. Off-target effects The major concern about off-target editing persists in TP53 restoration because unintended modifications could potentially lead to tumorigenic effects. The development of high-fidelity Cas9 variants together with base-editing strategies has decreased the probability of unwanted editing events. The heterogeneous nature of GBM tumors requires not only TP53 but also multiple oncogenic driver targets for complete tumor suppression. Recent computational off-target prediction tools, combined with whole-genome sequencing of edited GBM cells, confirmed that newer Cas9 variants such as eSpCas9 and HypaCas9 reduced off-target mutations by nearly 90%. This precision is crucial in a clinical setting. 5. Preclinical outcomes and translational potential Studies using animal models of GBM that received CRISPR-based TP53 restoration treatments demonstrated better survival outcomes than untreated controls. The path to clinical implementation faces two main obstacles, which involve improving delivery methods and establishing long-term safety measures.
• Conclusion: The therapeutic method of CRISPR-based TP53 function restoration shows great promise for glioblastoma treatment because it enables direct tumor suppression through the restoration of a fundamental cancer-preventing gene. The preclinical development of CRISPR technology, delivery vectors, and combination therapy approaches indicates promising potential for future clinical applications. The development of precise editing methods and targeted delivery systems needs further improvement to establish TP53 restoration as a practical treatment option for glioblastoma patients.
• Keywords: CRISPR, TP53, glioblastoma, gene editing, tumor suppression