Gene transfer to the brain: emerging therapeutic strategy in psychiatry?

In the past 5 years, gene transfer strategies have increasingly been integrated into investigations of brain function with focus on cellular and molecular mechanisms of neuronal development, plasticity, and degeneration. These techniques are also under study as prospective treatment strategies for neurodegenerative disorders including Parkinson’s and Alzheimer’s disease. There has been considerable progress in the development of efficient and safe viral vectors for the delivery of transgenes directly to brain cells, and of transplantation techniques for neuronal, nonneuronal, and progenitor cells that have been genetically modified to release therapeutic gene products in the brain. New insights into the structure and organization of gene promoters and associated regulatory elements indicate a high degree of modularity and the design of a recombinant transcriptional apparatus that may allow developmental regulation and tissue-restricted expression to avoid unwanted side effects of the gene product, as well as the modulation of its expression by administered drugs in a therapeutic setting, is now an achievable goal. Based on an improved understanding of technologies that allow the addition, alteration, or elimination of individual genes to create transgenic animal models, constitutive or conditional gene knockout strategies are likely to increase our knowledge of which gene products are involved in the etiology and pathophysiology of psychiatric disorders, such as schizophrenia. Paralleling the refinement of gene transfer techniques and the fading dogma of a limited capacity of neurons for regeneration, reproducibility, and plasticity, it is currently being realized that gene therapy may also be applicable to genetically complex, non-mendelian disorders. While the concept of therapeutic gene transfer in severe neurodegenerative and psychiatric disorders is still in its theoretical infancy, the technical prerequisites are being developed at an extraordinary pace, thus raising not only modest hopes for a beneficial application of these novel treatment strategies in some forms of chronic-progressive, consistently debilitating, and treatment-refractory psychosis, but also intensifying widespread ethical implications and public concerns regarding its potential for enhancement of normal CNS function.