alexa Gene therapy for human malignant brain tumors.
Genetics & Molecular Biology

Genetics & Molecular Biology

Journal of Genetic Syndromes & Gene Therapy

Author(s): Rainov NG, Ren H

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Abstract PURPOSE: Brain tumors were the first human malignancy to be targeted by therapeutic transfer of nucleic acids into somatic cells, a process also known as gene therapy. Malignant brain tumor cells in the adult brain have some unique biologic features, such as high mitotic activity on an essentially postmitotic background and virtually no tumor spread outside of the central nervous system. Brain tumors seem therefore to offer major advantages in the design of tumor-selective gene therapy strategies, and the role of gene therapy in malignant glioma has been investigated since the late 1980s, initially in numerous laboratory studies and later on in clinical trials. DESIGN: Retrovirus has been one of the earliest recombinant virus vectors used in brain tumors. Experiments in cell culture and in animal models have demonstrated the feasibility of retrovirus-mediated transduction and subsequent killing of glioma cells by toxic transgenes. Phase I and II clinical studies in patients with recurrent malignant glioma have shown a favorable safety profile and some efficacy of retrovirus-mediated gene therapy. However, the only prospective, randomized, phase III clinical study of retrovirus gene therapy in primary malignant glioma failed to demonstrate significant extension of progression-free or overall survival. Adenovirus- and herpes simplex virus type 1-based vectors have been actively investigated along with retrovirus, but their clinical use is still limited, mostly because of safety concerns. To increase efficacy, novel generations of therapeutic adenovirus and herpes simplex virus type 1 rely more on genetically engineered and tumor-selective lytic properties and less on the actual transfer of therapeutic genes. CONCLUSIONS: The failure of most clinical gene therapy protocols to produce a significant and unequivocal benefitto brain tumor patients seems to be mainly due to the low tumor cell transduction rates observed in vivo, but it may also depend on the respective physical delivery strategy of the vector. Standard radiologic criteria for assessing the efficacy of clinical treatments may also not be fully applicable to the specific metabolic changes and blood-brain barrier permeability phenomena caused in brain tumors by virus-mediated gene therapy. Clinical trials in malignant glioma have nevertheless produced a substantial amount of data and have contributed to the continuous improvement of vector systems, delivery methods, and clinical protocols.
This article was published in Cancer J and referenced in Journal of Genetic Syndromes & Gene Therapy

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