siRNA-Therapeutics

Since the revolutionary discovery of RNA interference (RNAi), remarkable progress has been made in understanding and exploiting the gene silencing mechanism, particularly in the field of small interfering RNA (siRNA) therapeutics (Hu B et al. 2019). The goal for siRNA therapeutics is to induce sustained, potent, and specific silencing for a defined genetic target. Here, therapeutic safety is a major concern. While the "off-target" effect of siRNA is an important issue that is being addressed by improving knowledge in this area, the long-term safety of siRNA is not yet assured. Thus, many challenges, such as rapid degradation, poor cellular uptake and off-target effects, are being overcome to bring these molecules into clinical trials (Wittrup A et al. 2015).

siRNA therapeutics have a good chance to be included in clinical care as a new class of drugs in the near future, twenty years after the discovery of RNAi (Hu B et al. 2019). Small interfering RNAs (siRNAs) can be used to turn off specific tumor genes (principle: turn off the gene, you can turn off the cancer) that induce deleterious or abnormal proteins (Subhan MA et al. 2019).Despite the tremendous potential benefits, the major challenges with most siRNA therapeutics remain unchanged - safe, efficient and targeted delivery of siRNA.

Here, the main obstacle to the use of siRNA therapies in clinical practice arises and that is the lack of an effective delivery system that protects the siRNA from degradation by nuclease, transports it to the tumor cell and releases it into the cytoplasm of the targeted cell without producing adverse effects. Thus, special carriers are needed to allow the siRNA s to enter the cell (Kanasty R et al. 2013). Advances for targeted drug delivery emerged in the use of various nanoparticles. This involves liposomes, polymeric nanoparticles, dendrimers, inorganic nanoparticles, exosomes and red blood cells.

A smaller number of phase I clinical trials have now been completed in patients with solid tumors. siRNA therapeutics have several distinct advantages over conventional pharmaceutical drugs. It is relatively easy to synthesize and produce siRNA on a large scale. Thus, they can be used as a broad biological tool with which almost all genes and their deleterious or abnormal proteins can be potentially suppressed. In the past, the progress of siRNA treatment occurred mainly in indications that are treatable by local siRNA administration. Eyes and lungs are promising tissues for local administration of naked siRNA. This is especially true for ophthalmological indications, which is reflected in the high number of clinical studies in this field. It is therefore not surprising that the first siRNA therapeutics ready for approval are intended for ophthalmology.

1. Hu B et al (2019) Clinical advances of siRNA therapeutics. J Gene Med 21:e3097.
2. Kanasty R et al (2013) Delivery materials for siRNA therapeutics. Nat Mater 12:967-977.
3. Saw PE et al.(2020) siRNA therapeutics: a clinical reality. Sci China Life Sci 63:485-500.
4. Subhan MA et al. (2019) Efficient nanocarriers of siRNA therapeutics for cancer treatment. Transl Res 214:62-91.
5. Wittrup A et al (2015) Knocking down disease: a progress report on siRNA therapeutics. Nat Rev Genet 16:543-552.