RNAi also holds promise for the clinic. Since siRNAs and shRNAs result in sequence-specific gene silencing, in theory they could function as small molecule inhibitors for use in the treatment of human disease. Although delivery is a key issue in general, certain organs such as the liver appear to be readily transferable by noninvasive techniques in mouse models (see McCaffrey et al. 2002; Song et al. 2003). Moreover, it is conceivable that they could be used in therapies requiring allele-specific or exon-specific targeting events (for example see Brummelkamp et al. 2002b). Intriguingly, the first clinical trials using RNAi-based therapies are currently underway for age-related macular degeneration (Check 2005; McFarland et al. 2004) and respiratory syncytial virus infection (Bitko et al. 2005). In addition, many groups are attempting preclinical development of RNAi-based therapies for other viral diseases (Rossi 2006; Dykxhoorn and Lieberman 2006), neurodegenerative disorders (Raoul et al. 2006), and cancers (Pai et al. 2006).
In vitro, RNAi has proved effective at inhibiting replication of many infection viruses including human immunodeficiency virus (HIV) (Jacque et al. 2002; Lee et al. 2002; Novina et al. 2002), hepatitis C (Kapadia et al. 2003; Randall et al. 2003), rotavirus (Dector et al. 2002), y-herpesvirus (Jia and Sun 2003), and influenza (Ge et al. 2003). Thus, efficient delivery of siRNAs or shRNA could be used to target viral transcripts directly to reduce viral loads in patients.
Yet another medical application would make use of stably expressed shRNAs. It has been suggested from the study of HIV-resistant populations that removal of the CCR5 and CXCR4 co-receptors may confer resistance to HIV infection (reviewed in Doms and Trono 2000). The use of self-inactivating retroviruses expressing shRNAs targeting these receptors could in theory cure this disease, at least during the early to middle stages when stromal support cells are not ravaged, if shRNAs were incorporated into hematopoietic stem cells ex vivo and then reintroduced into patients.
Given the tremendous potential, it is likely that RNAi will find its way into the clinic in some capacity. Only time will tell whether RNAi represents a "miracle" tool for disease research or merely a step beyond existing antisense technologies.
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