target range 19-25
too short – unspecified binding
too long – inflammatory immune response (recognized as viral RNA – TLR3/8/9 activation)
- high “U” content (recognized by TLRs) should be avoided
- shorter (< 24 bp) or chemically modified siRNA can be used (preventing activated protein kinase) and 3′-overhangs allow evasion from retinoic acid inducible gene I receptor immune sensing.
- GC content of an siRNA is addressed by algorithms and its range should be between ~30 and 60%
- selecting regions in the open reading frame about 50–100 nucleotides downstream of the start codon is recommended
Therapeutic Delviery
- RNA prone to rapid degradation (enzymatic and non)
- half-life of chemically unmodified naked siRNAs in the bloodstream is only ~ 5 minutes
- delivery strategies has been a major bottleneck
- systemic application, the liver as a target organ is comparatively easy to reach and at the forefront of the development
Present clinical approval
- limited to hepatocyte delivery
- lipid-based nanoparticles (LNPs) for delivery
Positive outlooks:
- siRNA production is easier and cheaper as compared with antibodies, thus making them competitive also price wise, and siRNA therapeutics may come with advantages regarding the mode of administration and the dosing period
- evolocumab vs inclisiran – latter cheaper to synthesize and is less frequent.
Need further exploration of siRNA drugs beyond the liver,
Readjudication 