Using CRISPR-Cas9 to Target EGFRvIII and SIRP-ɑ for Glioblastoma Treatment

Abstract

Glioblastoma (GBM) is an aggressive grade 4 brain tumor with a poor prognosis, with the 5-year survival rate remaining at a mere 5%. Standard first-line treatment consists of maximal safe resection followed by concomitant daily temozolomide with radiotherapy. However, tumor recurrence is frequent, and second-line treatments are lacking. While new therapies have been intensely studied, challenges with delivery across the blood-brain barrier (BBB) have largely hampered efforts to develop new efficacious glioblastoma treatments. The development of gene therapy like CRISPR-Cas9 to treat GBM is consequently still in the early stages. This review delves into how nanoparticles could be utilized to deliver CRISPR-Cas9 across the BBB into the tumor microenvironment and effectively edit both glioblastoma cells and tumor-associated microglia/macrophages (TAMs). This review will discuss the prevalence of the EGFRvIII mutation in GBM cells and its significant role in facilitating cell proliferation and the evasion of apoptosis, analyzing EGFRvIII as a potential target for gene knockout through CRISPR editing. Further, the immunosuppressive tumor microenvironment that characterizes GBM will be described, with an explanation of how TAMs contribute to tumorigenesis through their M2 polarization. Finally, the review will analyze the importance of the CD47/SIRP-α axis to the pro-tumorigenic nature of TAMs. It will study the possibility of disrupting SIRP-α expression in TAMs through CRISPR-Cas9 as a potential immunotherapy for GBM. Overall, this review will outline how the use of CRISPR-Cas9 to knock out EGFRvIII in GBM cells and SIRP-α in TAMs could potentially transform GBM treatment and substantially improve prognosis in patients.