Welcome to the exciting world of investigational new therapeutics based on nucleic acid chemistry. Please feel free to browse our website on microRNA whenever you like, file a comment or make suggestions to improve our internet presentation on microRNA. This is only a collection of thoughts about microRNAs, an accumulation of ideas, and we make no claim to cover this topic completely.
Since the discovery of small nucleic acid molecules as a novel tool to fight endemic diseases, research activities were exploded: antisense oligonucleotides to downregulate gene transcription in the nucleus, small interfering RNA (siRNA) to downregulate gene translation in the cytoplasm, microRNA (miRNA) also to downregulate gene translation, and many others were characterized both in vitro and in vivo. It would go beyond the scope of this website to enumerate all the R&D institutes and biotechnology industries which have been dealing with the development of microRNA as a drug.
MicroRNA molecules are naturally transcribed RNA, which is processed from a precursor into the 22-25 nt bioactive polynucleotide. In the last decade, microRNA has been discovered to play a significant role in post-transcriptional gene regulation in allmost all organisms and cell types. The development of new technologies like next generation sequencing (NGS) opened the possibility to uncover microRNA expression patterns among many tissues, organs, or even at the single cell type level. Small interfering RNA (siRNA) is also to downregulate gene regulation on the translational level, and is also found in transcriptomes of many species. Gene regulation mechanisms are quite the same like for microRNA, you might say.
Yes, right you are, but there is one difference which makes the biotech industry switch from siRNA drugs to microRNA therapeutics: the off-target effects. Small interfering RNA (siRNA) was supposed to downregulate only one target transcript, which prompted the biotech industry to push numerous siRNA drugs through preclinical development into the clinic. Let´s assume one siRNA drug was successfully characterized in toxicology studies, thanks to the pioneering work of companies like ISIS Pharmaceuticals or Archemix this is not an obstacle in these days. And even if local authorities approved the drug for a phase I clinical trial, it was still hard to demonstrate bioactivity of siRNA in vivo:
(1) intracellular delivery of bioactive double-stranded siRNA into the target organ is still a challenge; (2) modelling the toxicological profile of suitable siRNA vehicles to shuttle the drug to the target organ is still not completely solved; (3) this can be accompanied with small therapeutic windows, often too small…; (4) and finally, the lack of efficacy in vivo, particularly in cancer models. If you managed to demonstrate down-regulation of your target gene in vivo, and even if you could demonstrate RNA interference in vivo by techniques like Rapid Amplification of cDNA Ends (RACE), there often was still a lack of efficacy (more RACE thoughts here…).
Another major problem which arose from all of these problems is the search for suitable surrogate markers to demonstrate successful treatment with the nucleic acid drug. If siRNA is supposed to downregulate only one gene in only one specific target organ for efficacy, is it astonishing you will have problems to find any sign of successful treatment?
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