Antisense therapeutic agents synthesis

RNAi technology has obvious therapeutic potential as an antisense agent, and initial therapeutic targets of RNAi include viral infection, neurological diseases and cancer therapy. The synthesis of dsRNA displaying the desired nucleotide sequence is straightforward. However, as in the case of additional nucleic-acid-based therapeutic approaches, major technical hurdles remain to be overcome before RNAi becomes a therapeutic reality. Naked unmodified siRNAs for example display a serum half-life of less than 1 min, due to serum nuclease degradation. Approaches to improve the RNAi pharmacokinetic profile include chemical modification of the nucleotide backbone, to render it nuclease resistant, and the use of viral or non-viral vectors, to achieve safe product delivery to cells. As such, the jury remains out in terms of the development and approval of RNAi-based medicines, in the short to medium term at least. 

These three drugs illustrate both the hope and the frustration that is experienced with this class of therapeutics. The antisense mechanism works in the cells, and protein synthesis can definitely be inhibited. Getting from cell culture observations to useful and effective therapies, however, is a long road, and several seemingly useful antisense agents have fallen by the wayside when tested in randomized, double-blind trials. Clearly, attention must be paid to getting the dosing sohedule, formulation, and route of administration optimized. 

---