Therapeutic Prospects of mRNA-Based Gene Therapy for Glioblastoma

Abstract

The treatment of glioblastoma has been a big challenge for decades in the oncological field mainly owing to its unique biological characteristics, such as high heterogeneity, diffusing invasiveness, and capacity to resist conventional therapies. The mRNA-based therapeutic modality holds many superior features, including easy manipulation, rapid and transient expression, and adaptive convertibility without mutagenesis, which are suitable for dealing with glioblastoma's complexity and variability. Synthetic anticancer mRNAs carried by various vehicles act as the ultimate attackers of the tumor across biological barriers. In this modality, specifically targeted glioblastoma treatment can be guaranteed by adding targeting molecules at certain levels. The choice of mRNA-bearing vehicle and administration method is a fully patient-tailored selection. This review covers the advantages and possible limitations of mRNA-based gene therapy, the in vitro synthesis of mRNA, the feasible methods for synthetic mRNA delivery and clinical therapeutic prospects of mRNA-based gene therapy for glioblastoma.

Antisense technology: A review

“…Since ds ASOs or siRNAs are comprised of the same building blocks, the medicinal chemistry created to modify ASOs served as the basic chemical tool kit for siRNAs as well (10,13,14,34,35). Because these advances have been stochastic, they have been dubbed second generation and generation 2.5 chemistries (3,4) More recently with the success of GalNAc conjugation in targeted delivery of both ss PS ASOs and ds PS containing siRNAs (1,(3)(4)(5)10,35), focus has shifted to targeted delivery to other tissues. Additionally, because of breakthroughs in understanding the molecular mechanisms by which PS ASOs induce toxicities, site specific modifications have evolved (3,5,36).…”

In vivo gene delivery mediated by non-viral vectors for cancer therapy

“…Therefore, an efficient plasmid DNA delivery system is needed to protect the plasmid outside the cells, particularly against degrading enzymes, enhance their cellular uptake, preferably to the target cells and improve their pharmacokinetic properties for in-vivo applications. Since pDNA delivery has shown some difficulties particularly in terms of in-vivo applications, an alternative strategy to improve the gene expression level is mRNA therapy [33]. mRNA therapy has shown great advantages compared with pDNA in recent years [34].The site of action for mRNA is cytoplasm, whereas the pDNA must be entered to cell nucleus for efficient gene expression [35].…”

Exosomes for mRNA delivery: a novel biotherapeutic strategy with hurdles and hope

“…Exogenously delivered-mRNA has gained enormous attention due to its ability to encode any types of therapeutic proteins, including cytosolic, intra-mitochondrial, transmembrane, and secreted proteins [ 3 ]. In recent years, the potential therapy for various genetic defects has determined by a single gene, such as alpha-1 antitrypsin deficiency (AATD) [ 4 ], cystic fibrosis [ 5 ], and other monogenic disorders [ 6 ], as well as genetic diseases [ 7 ], brain diseases [ 8 ], infectious disease [ 9 ], cancers [ 10 ], etc. mRNA-based gene therapy is more advantageous, including no need any nuclear localization, and therefore no risk of genomic integration compared to classical gene therapy.…”

“…Immunogenicity of therapeutic mRNA not only was improved by the incorporation of modified nucleotides [ 11 ] but also was significantly reduced higher efficiency combined with enhanced safety by the carrier with minimal immunogenicity, protection of mRNA degradation by nucleases, ability to pass through the phospholipid membrane, underlie efficient release from the cargo [ 10 ]. Moreover, an appropriate carrier enables repeated dosing without any cytotoxicity to achieve a sufficiently high quality of encoded protein, which will improve therapeutic efficiency [ 12 ].…”