Abstract

Small interfering RNA (siRNA) are small non-coding molecules of double-stranded RNA which are capable of accessing ‘undruggable’ targets and consequently facilitating the treatment of previously untreatable diseases. siRNA are an unique class of therapeutics which target and neutralise mRNA, thereby reducing the production of specific proteins involved in disease pathology.

Cellular uptake is critical to the functioning of the siRNA and can be limited by enzymatic degradation and immune recognition, especially during blood circulation. Consequently, cellular uptake of siRNA is one of the challenges facing this group of therapeutic agents and drug delivery system, such as conjugation, need to be considered during pharmaceutical development.

There is currently no specific regulatory guidance on siRNA. However, the European Medicines Agency (EMA) has published a ‘Concept Paper on the Establishment of a Guideline on the Development and Manufacture of Synthetic Oligonucleotides’.

While siRNA have several highly desirable and unique attributes, there are also challenges for successful development, including drug delivery to the site of action, stability, and potential safety issues related to off-target effects and immunogenicity, which may be exacerbated by instability of the siRNA. Conversely, the favourable attributes include the ability to target a specific gene by protein suppression of that gene’s mRNA.

To-date several siRNA drugs have been approved for managing rare metabolic conditions and there are numerous products in clinical development.