RNA-mediated interference (RNAi) is a powerful tool for experimental manipulation of gene expression and is widely used to investigate gene function both in vitro and in vivo. RNAi refers to an evolutionarily conserved cellular mechanism for sequence-specific post-transcriptional gene silencing, in which double-stranded RNAs promote selective degradation of homologous cellular mRNAs. Because RNAi-based techniques can be employed to reduce expression of specific genes, this approach holds great promise as a therapy for diverse diseases, including devastating neurodegenerative disorders such as Alzheimers, Parkinsons, and Huntingtons diseases and amyotrophic lateral sclerosis (ALS). Importantly, in recent years RNAi has also emerged as a key tool in target identification and validation studies designed to complement traditional (i.e., small molecule-based) drug development strategies. These studies harness the power of RNAi-mediated reverse genetics to probe disease-associated pathways in both cell-based and animal models, and thus may provide critical data needed to focus drug development efforts around disease-relevant targets. This review highlights recent progress in the preclinical development of RNAi-based therapeutics for neurodegenerative disease and discusses the particular challenges that disorders of the central nervous system (CNS) pose for this approach. It further describes current applications of RNAi techniques for target identification and validation studies and underscores the importance of this methodology to developing treatments for neurological diseases.
Keywords: RNAi, siRNA, neurodegeneration, central nervous system (CNS) delivery, gene therapy, target validation