Gene transfer and delivery in central nervous system disease

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.