The 14th Tokyo Metropolitan Institute of Medical Science Symposium: Bioengineering for Drug Discovery

March 17th (Monday), 2025, 13:00 – 17:00

Tokyo Metropolitan Institute of Medical Science Auditorium

https://www.igakuken.or.jp/public/sympo/sympo14.html

“Principles and applications of optically controllable mononegaviruses”

Makoto Takeda, The University of Tokyo

Recent advances in optogenetics have opened new avenues for applications in cutting-edge science and medicine. The use of genetically modified viruses has expanded into diverse fields, including cancer therapy, regenerative medicine, and vaccine development.

For many years, we have studied mononegaviruses, which possess a non-segmented, negative-sense RNA genome. This group includes measles virus, rabies virus, respiratory syncytial virus (RSV), Ebola virus, and other viruses of major medical importance. Among these, measles virus has been utilized in multiple contexts, such as vectors for cancer therapy, polyvalent vaccines, and regenerative medicine. Notably, numerous clinical trials are being conducted overseas using measles virus as an oncolytic vector.

We developed a novel viral vector platform by incorporating a light-responsive protein (Magnet) into the polymerases of mononegaviruses, enabling precise light-dependent control of viral gene expression and replication (Tahara et al., 2019, PNAS). This technology has already been successfully applied to measles virus, rabies virus, and parainfluenza virus, and ongoing studies are focused mainly on applications as oncolytic vectors. By spatiotemporally controlling viral replication with light, we achieved the seemingly contradictory properties of inducing strong cytotoxicity against target cells while maintaining complete safety.

Specifically, we engineered a measles virus genome carrying light-control functionality into a bipartite (segmented) form, thereby increasing tolerance for insertion of foreign genes while also enhancing viral replication capacity. In addition, we modified receptor specificity to permit infection of a wide range of cancer cells, eliminated the original tropism for immune cells, and enhanced the cytolytic activity of the virus. The engineered viruses exhibited no replication in darkness but showed strong replication and cytotoxicity upon light exposure. Using this system, we successfully reduced or completely eliminated human tongue cancer xenografts implanted on the tongues of nude mice.