In recent years, gene therapy drugs have finally been approved in Europe, the U.S., and Japan. In parallel with this, advances in genome editing technologies have enabled therapeutic strategies by gene knockout and gene repair, which were difficult with conventional so-called gene addition therapy. Worldwide, over 30 clinical trials of genome editing therapy have already been conducted, and some protocols have shown not only safety but also therapeutic efficacy. In the clinical application of genome editing, in addition to the technical hurdles of conventional gene therapy, there are problems specific to genome editing technology, such as the risk of introducing DNA mutations due to off-target activity of enzymes and the immune response to the artificial nucleases. It is necessary to consider the objective risk and benefit in comparison to existing therapeutic protocols. It is also essential to further develop technologies for therapeutic application in a wider range of diseases.
The development of oligonucleotide therapeutics (ONTs) has advanced recently. Various ONTs (e.g., antisense oligonucleotides, small-interfering RNA, and microRNA) exert their pharmacological effects via hybridization with mRNA sequences, and they can also bind to unintended mRNA sequences owing to sequence homology. For this reason, the safety of ONTs should be evaluated by judging hybridization-dependent on- and off-target toxicity in preclinical studies. As the off-target toxicity is unique to ONTs, it is difficult to assess their safety with the current guidelines established for small molecules and biotechnology-derived pharmaceuticals; thus, several research groups, such as the Oligonucleotide Safety Working Group in the Drug Information Association (DIA), have proposed concepts for the preclinical safety evaluation of ONTs. Although there are currently no specific International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines for ONTs, the ICH S6 guideline states that “the principles outlined in this guidance may also be applicable to oligonucleotide drugs.” Recently, a preclinical safety guideline for ONTs has been developed by a Japanese working group to address the issues associated with the ICH S6. Here, the preclinical safety assessments of mRNA-targeting ONTs are discussed based on this guidance.