Antisense Oligonucleotides for Rapid Translation of Gene Therapy in Glioblastoma

Abstract

Purpose: The limited efficacy of current treatments for malignant brain tumors necessitates novel therapeutic strategies. This study aimed to assess the potential of antisense oligonucleotides (ASOs) as adjuvant therapy for high-grade gliomas, focusing on their CNS penetration and clinical translation prospects.

Methods: A comprehensive review of the existing literature was conducted to evaluate the implications of ASOs in neuro-oncology. Studies that investigated ASO therapy's efficacy, CNS penetration, and safety profile were analyzed to assess its potential as a therapeutic intervention for high-grade gliomas.

Results: ASOs present a promising avenue for enhancing targeted gene therapies in malignant gliomas. Their potent CNS penetration, in vivo durability, and efficient transduction offer advantages over conventional treatments. Preliminary in vivo and in vitro studies suggest ASOs as a viable adjuvant therapy for high-grade gliomas, warranting further exploration in clinical trials.

Conclusions: ASOs hold significant promise as adjuvant therapy for high-grade gliomas, offering improved CNS penetration and durability compared with existing treatments. While preliminary studies are encouraging, additional research is needed to establish the safety and efficacy of ASO therapy in clinical settings. Further investigation and clinical trials are warranted to validate ASOs as a transformative approach in neuro-oncology.

Keywords: adjuvant therapy; antisense oligonucleotides; blood–brain barrier; brain tumor; central nervous system; gene therapy; high-grade gliomas.

Figure 1

ASOs can decrease the formation of protein products by blocking the addition of the 5′ cap or the poly-A tail or by causing alternative splicing to recently transcribed mRNA. ASOs can similarly block translation by inhibiting the binding of ribosomes to mRNA or by recruiting RNase and causing the degradation of RNA.

Figure 2

Chemical modifications of ASO include backbone remodeling, 2O’ substitutions, and locked nucleic acids. Chemical modifications of ASO work to stabilize the product and increase the efficacy.