| Activity |
• Nuclear and cytoplasmic |
• Mainly cytoplasmic |
| Design |
• Chemical modifications required |
• Active in vivo as chemically modified or in genetic vectors |
|
• Can be more extensively chemically modified than siRNA |
• More limited chemical modifications can be introduced |
|
• Single-stranded (smaller) |
• Mainly double-stranded (larger molecules) |
|
• Relatively large set of ONs must be tested to find active ones |
• Design rules are well established |
| Efficiency |
• Lower or equal to that of siRNAs in cell culture, depending on the chemical modification pattern used |
• Very high efficiency in cell culture, due to typical catalytic mode of action |
|
• Better efficiency in vivo than siRNAs |
• Moderate sensitivity for target structure |
|
• Might be more sensitive for target structure than siRNAs |
• RISC complex facilitates finding targets and hybridizing |
|
• It is unknown whether it finds and hybridizes to targets unassisted |
|
| Off-target (sequence specific) |
• Moderate risk |
• High risk as activity is based on ‘seed’ pairing |
|
|
• Improvement in siRNA design overcame some off-targeting |
|
|
• Heterogeneous cleavages in shRNAs and shmiRs generate unwanted siRNAs |
| Off-target (non-sequence specific) |
• High risk of immunostimulatory responses through interactions with toll-like receptors (TLRs) |
• Possible disturbance of the endogenous miRNA pathway |
|
|
• Activation of pathways by dsRNAs |
| Strategy development |
• Generally more advanced in clinical trials, as developed since the late 1970s |
• Developed since 2000s |
|
• For polyQ disorders tested in last few years |
• Extensively tested in cell culture and rodent models of polyQ diseases |
