Gene Therapy for High-Grade Glioma

Abstract

High-grade glioma is the most frequently occurring primary brain tumor and is associated with a poor prognosis. Current treatment regimens have had only a modest effect on the progressive course despite recent advances in surgery, radiotherapy, and chemotherapy. Gene therapy for brain tumors represents a novel and promising therapeutic approach and has been investigated clinically for the last two decades. The strategies of gene therapy include suicide gene therapy, immune gene therapy, oncolytic viral therapy, tumor suppressor gene therapy, and antisense therapy. Here, we review gene therapy approaches considering the clinical results, limitations, and future directions.

Genetic and Immunology of Brain Tumors

“…Non-viral methods provide certain advantages over viral methods, such as simple large scale production and low host immunogenicity, however small levels of transfection and expression of the gene are a disadvantage of this methods (Iwami et al, 2010 (Mut & Ziyal, 2010). 1.…”

“…Despite these factors minimizing central nervous system (CNS) immune function, a highly adapted system of immune surveillance presents, and effective immune responses can occur in the enzyme prodrug ('suicide gene') therapy, oncolytic therapy, replacement/ therapeutic gene transfer, and antisense therapy (Bansal& Engelhard, 2000). Many of them have been attempted both experimentally and in clinical trials (Iwami et al, 2010;Licht et al, 1996;Lun et al, 2010;Pedersini et al, 2010;Schmidt et al, 2011;Steffens et al, 2004;Yawata et al, 2011). Mainly these approaches are based on previously established anti-neoplastic principles, like prodrug activating enzymes, inhibition of tumor neovascularization, and enhancement of the normally infirm anti-tumor immune response.…”

“…Mainly these approaches are based on previously established anti-neoplastic principles, like prodrug activating enzymes, inhibition of tumor neovascularization, and enhancement of the normally infirm anti-tumor immune response. The strategies of gene therapy can be categorized as follows (Mut& Ziyal,2010 Immune gene therapy aims to enhance the T cell mediated immune responce againts to brain neoplasms by using genetically modified T cell therapy, vaccination therapy and cytokine therapy (Iwami et al, 2010). Cytotoxic therapy is mainly consist of either delivering of gene or virus therapy (Aboody et al, 2008;Aghi & Chiocca, 2006;Candolfi et al, 2009;Kroeger et al, 2010;Lawler et al, 2006).…”

“…In the first one, the vector is derived from a virus from which all or most of its genome has been removed, so minimizing the toxicity and retaining the gene delivery efficiency. In the second, only select viral genes are deleted or mutated so that viruses can replicate in and lyse tumor cells selectively (i.e., oncolytic viral therapy) (Iwami et al, 2010). genes are inserted into the tumor cells.…”

Hypoxia Responsive Vectors Targeting Astrocytes in Glioma

“…Mostly viral vectors have been used as vehicles to carry exogenous genes into human cells since they bind to the host cell and introduce genetic material into the cytoplasm or nucleus as a part of their replication cycle. Viruses used in glioma gene therapy generally fall into two categories: replication incompetent viruses (from which all or most of its genome has been removed) and replication competent viruses (where select viral genes are deleted or mutated so that viruses can replicate and lyse tumor cells selectively) to minimize toxicity and retain gene delivery efficiency (Iwami et al, 2010). Adenoviruses (AdV) or retrovirus (RVs) have both been used in clinical trials to treat gliomas.…”