Viral vectors for gene delivery to the central nervous system.

Brain diseases with a known or suspected genetic basis represent an important frontier for advanced therapeutics. The central nervous system (CNS) is an intricate network in which diverse cell types with multiple functions communicate via complex signaling pathways, making therapeutic intervention in brain-related diseases challenging. Nevertheless, as more information on the molecular genetics of brain-related diseases becomes available, genetic intervention using gene therapeutic strategies should become more feasible. There remain, however, several significant hurdles to overcome that relate to (i) the development of appropriate gene vectors and (ii) methods to achieve local or broad vector delivery. Clearly, gene delivery tools must be engineered for distribution to the correct cell type in a specific brain region and to accomplish therapeutic transgene expression at an appropriate level and duration. They also must avoid all toxicity, including the induction of inflammatory responses. Over the last 40 years, various types of viral vectors have been developed as tools to introduce therapeutic genes into the brain, primarily targeting neurons. This review describes the most prominent vector systems currently approaching clinical application for CNS disorders and highlights both remaining challenges as well as improvements in vector designs that achieve greater safety, defined tropism, and therapeutic gene expression.

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