Emerging use of non-viral RNA interference in the brain

Psychiatric and neurological disorders are among the most complex, poorly understood and debilitating diseases in medicine. Abrogating gene function using knockout animals is one of the primary means of examining the pathophysiological significance of a given gene product and has been used successfully in models of neuropsychiatric disorders. However, the developmental compensations that may potentially arise from such approaches are problematic and difficult to assess. The recent discovery of RNAi (RNA interference), as a highly efficient method for gene knockdown, has opened up the possibility for its application in examining the potential role of genes in adult brain function and/or disorders. Recent efforts have focused on applying RNAi-based knockdown to understand the genes implicated in neuropsychiatric disorders. We have developed a method of gene knockdown involving chronic infusion of siRNA (short interfering RNA) using osmotic minipumps. We have silenced a number of genes including those for the serotonin and dopamine transporter. Such tailoring of tools that deliver RNAi in the brain will significantly aid in our understanding of the complex pathophysiology of neuropsychiatric disorders where there is an immensely unmet medical need.