The status of gene therapy for brain tumors

Abstract

The advent of gene therapy in the early 1990's raised expectations for brain tumor therapies; however, whereas clinical trials in patients with malignant gliomas provided evidence of safety, therapeutic benefit was not convincing. These early forays resembled the historical introductions of other therapies that seemed promising, only to fail in human trials. Nevertheless, re-study in the laboratory and retesting in iterative laboratory-clinic processes enabled therapies with strong biological rationales to ultimately show evidence of success in humans and become accepted. Examples, such as organ transplantation, monoclonal antibody therapy and antiangiogenic therapy, provide solace that a strategy's initial lack of success in humans provides an opportunity for its further refinement in the laboratory and development of solutions that will translate into patient success stories. The authors herein summarize results from clinical trials of gene therapy for malignant gliomas, and discuss the influence of these results on present thought in preclinical research.

Depletion of Peripheral Macrophages and Brain Microglia Increases Brain Tumor Titers of Oncolytic Viruses

“…The advent of OV therapy raised expectations for improved brain tumor treatments, but therapeutic benefit has not been convincing (10)(11)(12)(13)(14)(15)(16)(17). However, the strong biological rationale of this strategy underlies continuous laboratory restudy and new clinical trials.…”

“…The major barrier to virotherapy efficacy has been the inability to induce efficient intratumoral viral distribution. This is a common obstacle in brain tumor therapies but one unexpected with OVs because of their theoretical potential to replicate within cancer cells and spread throughout tumor (17). We and others have suggested that the activation of antiviral immune responses may be one factor responsible for the disappointing intratumoral viral propagation observed in vivo and that combined therapy with virus and immunosuppressive agents increased intratumoral spread and animal survival (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36).…”

“…However, clinical trials have shown OV to be safe but not effective (10)(11)(12)(13)(14)(15)(16)(17), possibly because viral replication was less than anticipated. In fact, OV can kill tumor cells grown in vitro with high efficiency (i.e., with input multiplicity of infection of 0.001-0.1).…”

Novel Gelatin–Siloxane Nanoparticles Multiple Modified by Cationic Peptide and Aptamers as Efficient Gene Vector

“…And as shown in Fig.2, transmission electron microscopy（TEM）demonstrated that the GS-PEG-TTA1/TAT NPs and GS-PEG-TTA1 NPs both had the characteristics of average size, dispersity and sphericity. Just as described by references [6]. In addition, the sizes and surface charge were examined with Nano-ZS zetasizer dynamic light scattering detector (Fig.3) Fig.3 that when adding plasmid into nanoparticles suspension, the diameter increased and the surface charge decreased, especially in the GS NPs group and GS-PEG-TTA1/TAT NPs group.…”

“…Recent years, some scholars point that gene therapy may be potential for curing both genetic and acquired disease [4,5]. Gene therapy, defined as the delivery of nucleic acids into the recipient's cells for therapeutic purposes, could have significant potential in the treatment of various CNS diseases [6].Although there is some advances in the field, delivery of nucleic acids to target cells and tissues with high-efficiency is still challenging. Synthetic, non-viral vectors are potential alternatives to viral vectors, and may overcome several problems encountered in viral vector-mediated therapy, including immune responses, limited DNA carrying capacity, recombination and high cost.…”