TITLE:
Gene therapy strategies for treating brain tumors: Retroviruses are still good candidates for therapeutic vectors
AUTHORS:
Toshio Yawata, Keiji Shimizu
KEYWORDS:
Gene Therapy; Malignant Glioma; Hsvtk; Retrovirus Vector; Bystander Effect
JOURNAL NAME:
Open Journal of Genetics,
Vol.3 No.2A,
June
26,
2013
ABSTRACT: Glioblastoma multiforme
(GBM) is the most common and aggressive primary brain tumor in adults. In the
past few decades, many efforts have been made to improve the prognosis of GBM,
however, with limited success. Many gene therapy strategies for GBM have been
developed and a few have progressed to clinical trials. Retroviral vectors have
superior features for gene therapy in brain cancers, including tumor specificity, immunogenicity, and longer half-life.
Early gene therapy trials in GBM patients based on transplantation of
retrovirus-producing cells into the brain failed to prove efficacious. Adenoviral
vectors, which can be prepared as high-titer virus solutions and undergo efficient
transduction in tumor cells, failed in clinical trials, likely due to
immunogenicity and instability of gene expression. Alternative therapeutics
such as oncolytic viruses that specifically
target and destroy cancer cells are currently under investigation. In
addition to novel vectors, retroviral vectors are still attractive candidates
for use in gene therapy against brain tumors. Since yields of properly-packaged
viral particles from virus-producing cells have been very limited so far, gene
therapy by direct injection of hightiter retroviral vectors into the patients’
brains was not possible. To overcome these disadvantages, a packaging cell line
that yields high-titer retroviral solutions was established by our group, enabling
the direct injection of massive retroviral vector stocks directly into the
brain. Mouse glioma models were effectively cured with a combination of a suicide
gene/ prodrug system and a highly-concentrated retrovirus solution. Preclinical
assessments, including that of replication-competent retroviruses and
tumorigenicity of the combination method, have confirmed the safety of the
highly-concentrated retrovirus solution. Addi tional studies are needed to
address the clinical utility of such combination gene therapies. Taken together, these data suggest that retroviral vectors
are still good candidates for development in gene therapy applications.