Regulating translation of synthetic mRNA to protein with light--Novel system developed by CiRA at Kyoto University

A research group led by Kyoto University CiRA Project Advisor Hideyuki Nakanishi (currently at Tokyo Medical and Dental University Institute of Biomaterials and Bioengineering) and Professor Hirohide Saito has developed two types of translational regulator (split CaVT, destabilizing CaVT) capable of regulating the translation of synthetic messenger RNA (mRNA) containing modified bases using light. Combining a normally repressed translation synthetic mRNA with split CaVT or destabilizing CaVT would activate cell-selective translation of the synthetic mRNA when illuminated. The research group developed the CaVT previously, a translational regulator protein that can be applied to controlling translation of synthetic mRNA containing modified bases. The findings were published in Cell Chemical Biology.

Synthetic mRNA is similar to DNA in that it delivers genes to be expressed in the target cell, but different in that it does not carry the risk of insertional mutagenesis in the genome. Therefore, it is expected to be very useful in genetic transfer with medical objectives such as genetic therapies and vaccines. However, compared to DNA, it is much more difficult to control the site of the genetic expression. This was especially notable in synthetic mRNA containing modified bases to avoid immune response.

The new system consists of three components: "low-molecular compounds activated by light," "translation regulator for activated compounds" and "synthetic mRNA with RNA motif bonded to a translation regulator." The introduction of synthetic mRNA can still provoke an immune response, but the synthetic mRNA used in this system contains modified bases that prevent immune response.

With this system, translation of protein from synthetic mRNA can be activated or suppressed by lighting up specific cells.

The result is that translation of synthetic mRNA containing modified bases can be specifically controlled by exposing certain locations to light, therefore expressing therapeutic genes in locations specific to the disease site. It is hoped that this will lead to new gene therapies that are both highly effective and avoid side-effects in healthy tissue.

Project Assistant Professor Nakanishi says, "Synthetic mRNA containing modified bases has been in the spotlight lately due to its use in Covid-19 vaccines, but it is hoped that its application will extend beyond vaccines to a range of other medical applications. This new light-regulated translational technology uses light that is not very biopermeable, therefore it cannot immediately be used in medicine, but we are aiming to develop RNA medicines that are effective with minimal side-effects, based on this concept."