Screening of siRNA Therapeutics

Because siRNA therapeutics act through a common mechanism of action, robust screening pipelines for a broad variety of targets and indications can be established with a minimum 

FIGURE 4.1 Chemical modifications to ribose sugar or phosphate linkages. BNA, bridged nucleic acid LNA, locked nucleic acid PMO, phosphorodiamidate morpholino oligomer. 

DISCOVERY AND DEVELOPMENT STRATEGIES FOR SMALL INTERFERING RNAs 

3 Lead Optimization of siRNA Lead identification can be visualized as an upside down pyramid (Fig. 4.2) where an initial set of siRNA are filtered through a set of assays in order to hone in on one or more lead designs. Lead optimization, in contrast, best fits the visnal metaphor of a diamond, whereby each potent lead is diversified throngh chemical modification of the nucleotides (Elbashir et al., 2001a Czaudema et al., 2003) and subseqnently refiltered. This process is very much iterative. In each round the 

4 Off-Target Analysis siRNAs can have a variety of off-target effects, including immune stimulation, interference with microRNA regulation, or off-target silencing due 

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