RNAi drugs: Next generation drugs?

Gene therapy aims to apply biotechnological techniques to correct a defective gene through administrating therapeutic nucleic acids or editing a defective gene. The approaches used in gene therapy include traditional transgene, genome editing, such as CRISPR/CAS9, RNA interference (RNAi) and antisense oligonucleotides (ASOs), etc. Gene therapy is promising as a main approach of disease treatment in the future. Particularly, RNAi is a potential rising-star in this field. RNAi is a biological phenomenon in which small RNA molecules inhibit gene expression at post-transcriptional level. There are two categories of RNA molecules, which include small interfering RNAs (siRNAs) and microRNAs (miRNAs). Both RNA types can induce gene silencing through distinct mechanisms, such as degrading mRNA, decreasing mRNA stability, or preventing protein translation. The major difference between siRNAs and miRNAs is that siRNAs are double stranded RNAs with completely paired sequences and high specificity for its targeted mRNA, whereas miRNAs are single stranded RNAs with incomplete complementary sequences and multiple targets on mRNAs. When compared with traditional therapeutic drugs which target defective proteins, siRNA and miRNA drugs offer advantages, such as higher specificity, lower toxicity, and easy manipulation of the defective genes of interest, etc. ASOs technique is another approach to silence a gene at the post-transcriptional level by several mechanisms including recruiting RNase H to cleave and degrade the targeted mRNA, alternative splicing, blocking translation, or binding to miRNA to regulate gene expression. The first-ever RNAi drug was approved in the United States and Europe in 2018, a significant milestone in pharma-cology which represents an era of a new type of drug. This event has been nominated as one of the top ten 2018 scientific breakthroughs. Apparently, it is expected that several other RNAi drugs will be approved for marketing in the near future. The first siRNA drug was used on a rare genetic disease that only affected about 50000 people worldwide. The major obstacle to widely-spread use RNAi drugs is the low delivery efficiency of small RNA molecules into cells or tissues. Various approaches have been developed for RNAi drug delivery in vivo including nanoparticles, cationic lipids, viruses, and polymers. However, they all have limitations for therapeutic applications. The first ASO drug was approved in 1998. Several other ASO drugs were approved in the following twenty years. However, the ASOs drugs have not become a mainstream drug yet due to some limitations other than delivery vehicle, such as adverse side effects from both on-target and off-target toxicities. The RNAi drugs and ASOs drugs may face similar problems in wide clinical applications. The approval of the first RNAi drug will greatly pave a way for the development of more RNAi drugs. We expect current technical hurdles in RNAi delivery will be resolved in the near future and RNAi drugs will become mainstream as next generation drugs.