EditorialsTherapies for hepatitis B: Where to from here?
Section snippets
Introducing RNA silencing
RNA silencing or posttranscriptional gene (PTG) silencing, is the process whereby double-stranded RNA (dsRNA) induces the sequence-specific degradation of homologous messenger RNA (mRNA). The current model of RNAi involves a multi-step process.3, 4 First, the initial dsRNA (>26bp) is cleaved by an RNAse III-like enzyme, termed Dicer, to generate 21–23nt fragments of siRNA. Second, an ATP-dependent RNA helicase recognizes these short duplexes and resolves the siRNA duplex into 2 single-stranded
RNAi-mediated inhibition of viral replication
In plants, PTG silencing and RNAi play critical roles in genome surveillance, protecting the cell from inappropriate expression of repetitive sequences and transposable elements, as well as a major antiviral defense mechanism.8 The ability to tap into this innate antiviral pathway to devise possible treatments against viruses is rapidly emerging as a new field of therapeutic intervention. To date, RNAi has been used effectively to inhibit the replication of several different pathogenic human
Delivery
A major impediment to using RNAi technology for therapeutic benefit has been the development of efficient delivery systems for siRNAs. However, several companies are developing clinically appropriate approaches to overcome this obstacle (see Nucleonics Inc. at www.nucleonicsinc.com). Previous methods relied on harsh lipid-based transfection reagents to introduce siRNAs into cells in culture and are either inefficient and/or unsuitable for use in animals. Interestingly, injected siRNAs have been
Resistance
The selection of resistant strains of poliovirus10 and HIV29 in cultures treated with specific siRNAs is a reminder that a single nucleotide mutation is all that is needed to allow the virus to escape the effect of a single specific siRNA. Emergence of siRNA resistance is a major concern that will need to be addressed, particularly for viruses encoding error-prone polymerases such as those of HIV-1 and HBV. In the study of Wu et al,2 sequence analysis of an HBV clinical isolate showed that a
Conclusions and future challenges
It is striking how rapidly the field has moved from an initial discovery phase to a stage where implementation and evaluation of siRNA technology in a therapeutic setting is expected sometime this year. However, our understanding of the biological mechanisms underlying RNAi lags behind the momentum to apply this technology to human diseases such as cancer and infectious diseases caused by HIV-1, HCV, and HBV. Clearly the objective, in the short term, is to improve viral delivery systems with
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