M. Maher Hulou and E. Antonio Chiocca
Bob S. Carter and E. Antonio Chiocca
Russell R. Lonser, Gregory J. Zipfel and E. Antonio Chiocca
Gordon Tang and E. Antonio Chiocca
Gene transfer offers the potential to explore basic physiological processes and to intervene in human disease. The central nervous system (CNS) presents a fertile field in which to develop novel therapeutic modalities to treat intractable and pervasive malignant tumors and neurodegenerative disease. The extension of gene therapy to the CNS, however, faces the delivery obstacles of a target population that is postmitotic and isolated behind a blood-brain barrier (BBB). Approaches to this problem have included grafting of genetically modified cells to deliver novel proteins or introducing genes by viral or synthetic vectors geared toward the CNS cell population. Direct inoculation and bulk flow, as well as osmotic and pharmacological disruption, have been used to circumvent the BBB's exclusionary role. Once the gene is delivered, myriad strategies have been used to affect a therapeutic result. Genes activating prodrugs are the most common antitumor approach. Other approaches focus on activating immune responses, targeting angiogenesis, and influencing apoptosis and tumor suppression. At this time, therapy directed at neurodegenerative diseases has centered on ex vivo gene therapy for supply of trophic factors to promote neuronal survival, axonal outgrowth, and target tissue function. Despite early promise, gene therapy for CNS disorders will require advancements in methods for delivery and long-term expression before becoming feasible for human disease.
James P. Basilion, Tomotsuga Ichikawa and E. Antonio Chiocca
The explosion of molecular techniques for gene discovery and their application to a variety of diseases has uncovered numerous gene abnormalities that can result in disease. These discoveries have provided the needed understanding and genetic materials to apply gene therapy approaches in the treatment of several diseases, including those of the central nervous system. A variety of different anticancer complementary DNAs (cDNA) have been shown to possess biological efficacy when used in the appropriate experimental setting. However, efficient and effective delivery of these cDNAs remains a major obstacle for future clinical applications. The focus of this review will be to describe the obstacles that impede the process of gene therapy and oncolytic viral therapy of brain tumors and to describe how important new discoveries derived from other disciplines are being used to address problems encountered in the gene/ viral therapy of this disease.