Imaging in Gene Therapy of Patients with Glioma

Abstract

Over 10 years ago, the first successful gene therapy paradigms for experimental brain tumors models have been conducted, and they were thought to revolutionize the treatment of patients with gliomas. Application of gene therapy has been quickly forced into clinical trials, the first patients being enrolled in 1994, with overall results being disappointing. However, single patients seemed to benefit from gene therapy showing long-term treatment response, and most of these patients bearing small glioblastomas. Whereas the gene therapy itself has been performed with high sophistication, limited attention has been paid on technologies, which (i) allow an identification of viable target tissue in heterogenous glioma tissue and which (ii) enable an assessment of successful vector administration and vector-mediated gene expression in vivo. However, these measures are a prerequisite for the development of successful gene therapy in the clinical application. As biological treatment strategies such as gene and cell-based therapies hold promise to selectively correct disease pathogenesis, successful clinical implementation of these treatment strategies rely on the establishment of molecular imaging technology allowing the non-invasive assessment of endogenous and exogenous gene expression in vivo. Imaging endogenous gene expression will allow the characterization and identification of target tissue for gene therapy. Imaging exogenously introduced cells and genes will allow the determination of the 'tissue dose' of transduced cell function and vector-mediated gene expression, which in turn can be correlated to the induced therapeutic effect. Only these combined strategies of non-invasive imaging of gene expression in vivo will enable the establishment of safe and efficient vector administration and gene therapy protocols for clinical application. Here, we review some aspects of imaging in gene therapy trials for glioblastoma, and we present a 'proof-of-principle' 2nd-generation gene therapy protocol integrating molecular imaging technology for the establishment of efficient gene therapy in clinical application.

Imaging-Guided Gene Therapy of Experimental Gliomas

“…February 15, 2007 potential therapeutic efficacy, which nevertheless remains either partial or occurs only in single patients with small tumors. Explanations for the limited therapeutic efficiency include the heterogeneity of target tissue (31), insufficient transduction efficiency (32), and interindividual variability of infectivity by vector particles due to different entry receptor status (8). Ongoing research focuses on the development of safe replication-conditional vectors and genetic approaches to target vascular and growth factor receptors and transforming growth factor-h, as well as to stimulate the immune response.…”

Imaging in neurooncology

“…136 Especially after the application of biologically active agents (gene therapy vectors, toxins), the value of conventional MRI to detect therapy-specific changes of tumor viability is limited 137 as reviewed previously. 138 In contrast, dynamic contrast enhanced MRI, as a surrogate marker for angiogenesis, is useful for monitoring antiangiogenic therapies in brain tumors. 139 Moreover, diffusion-weighted MRI detects therapy-induced water diffusion changes and has been suggested to provide an early surrogate marker for quantification of treatment response.…”

HMGA1 expression in human gliomas and its correlation with tumor proliferation, invasion and angiogenesis

“…Despite optimum treatment, median survival is only 12-15 months for patients with glioblastoma multiforme (GB), 2-3 years for patients with anaplastic astrocytoma (AA, WHO grade III), and 5-10 years for patients with diffuse astrocytoma (DA, WHO grade II) [3]. As a result of dramatic progress in understanding the pathogenesis and molecular mechanisms of proliferation, invasion, and angiogenesis of malignant gliomas, gene therapy is being developed as a more effective strategy in treatment [4][5][6][7]; it is, however, still very difficult to select proper tumor genes for targeted therapy.…”