Research

We have been continuously carrying out research into the development of fundamental gene therapy techniques. Our main research theme is the development and clinical application of gene and cell therapies using viral vectors as well as mesenchymal stromal cells for illnesses where fundamental therapies are still difficult, such as muscular dystrophy, stroke, and cancer.

Techniques related to various virus vectors we have engaged with include research into the implementation of adeno-associated virus (AAV) vectors. At present, AAVs are highly regarded as the prominent candidate vectors for gene therapy, whereas the greatest challenge in the full-scale rollout of the AAV vectors was that large-scale production methods for vectors standardized by production management, as part of the formulation of GCTP (Good Gene, Cellular, and Tissue-based Products Manufacturing Practice), had not yet been established. By overcoming various technical challenges, we have been developing original methods for the production of highly standardized AAV vectors. License transfer of the various techniques to the bio-industry is currently underway, and the large-scale production of GCTP preparations would be executed at viraI vector production plants with a view towards clinical application. The results of this research show the state of steady progress from fundamental research to clinical application towards a global rollout of gene therapies.

We have engaged in research into the development of gene therapies of genetic muscle disorders called muscular dystrophies that present with progressive muscle weakness and atrophy. Duchenne muscular dystrophy (DMD) has a relatively high incidence rate and serious clinical symptoms, although no effective treatment exists. Actually, the causative gene for DMD was identified as many as 30 years ago, and it is known that its occurrence results from disruption of the dystrophin gene on the X chromosome. To date, we have demonstrated the efficacy of additive gene transfer into various DMD model animals by the introduction of the micro-dystrophin gene using the above mentioned AAV vectors.
　For example, to investigate the details of the immune response accompanying AAV vector treatment, we have performed experiments in dog models, which have an immune response system more similar to that of humans than that of mice. As a result, it was observed that no remarkable adverse events or inflammatory reaction to the expression of the stabilized micro-dystrophin gene occurred over years to reconfirm the possibility of using AAV vectors for DMD gene therapies. Upon using infra-red monitors to observe the frequency of movement of the treated dogs in their cages, a dear increase in the values was found compared to those before the therapy. Pulmonary and cardiac dysfunction also improved. The fact that dogs have a similar virus clearance function to humans, lends considerable hope to use in human.

In addition to vector related researches, we have also been conducting researches using stromal cells called MSCs (mesenchymal stromal cells) to develop genetic therapy methods for cancer. MSCs have the property that they chase cancer cells in the body. Consequently, if MSCs are used as viral vector-producing cells, no matter where the cancer cells move, the MSCs will rapidly find and accumulate at the invisible cancer cells and produce the viral vector there. The method administers cells that produce virus at the site of the tumor tissues, instead of administering virus directly into the body. Regarding the advantages of utilizing MSCs in gene therapies, by using the hunting effect of MSCs, the viral vector component can be sent into permeating lesions such as those found in cancer. As a result, it is possible to reduce side effects and increase the concentration of the expression of therapeutic genes at the target tissue, as well as enabling the long-term, stable replenishment of protein within the lesion. It is hoped that, in the future, MSC gene therapies will play a role in patients where invasion or metastasis of cancer has made surgery impossible,

In addition to vector related researches, we have also been conducting researches using stromal cells called MSCs (mesenchymal stromal cells) to develop genetic therapy methods for cancer. MSCs have the property that they chase cancer cells in the body. Consequently, if MSCs are used as viral vector-producing cells, no matter where the cancer cells move, the MSCs will rapidly find and accumulate at the invisible cancer cells and produce the viral vector there. The method administers cells that produce virus at the site of the tumor tissues, instead of administering virus directly into the body. Regarding the advantages of utilizing MSCs in gene therapies, by using the hunting effect of MSCs, the viral vector component can be sent into permeating lesions such as those found in cancer. As a result, it is possible to reduce side effects and increase the concentration of the expression of therapeutic genes at the target tissue, as well as enabling the long-term, stable replenishment of protein within the lesion. It is hoped that, in the future, MSC gene therapies will play a role in patients where invasion or metastasis of cancer has made surgery impossible,

We would like to continue the research carried out to present into fundamental vector techniques, stromal cell techniques, molecular pathology analysis, and the gene therapies that make use of these. Additionally, so that these results can make it to clinical use, we would like to guide the standardization of therapies and preparation of clinical trials.

In recent years, "chimeric antigen receptor (CAR) T-cell therapy," a type of ex vivo gene therapy, has been approved for intractable blood cancers such as leukemia. CAR-T cells are given the ability to bind to and kill leukemia cells by transducing CAR genes. Current CAR-T therapy is an autologous transplantation in which the CAR genes are introduced into patients’ T cells and then returned to their hosts. Currently, "lentivirus vectors" are mainly used to transduce CAR genes. We are working to develop next-generation CAR gene therapies by utilizing our experiences of lentiviral vector application in leukemia and cancer research. In addition, lentiviral vectors, which are capable of expressing genes for extended periods of time, are drawing attention to in vivo gene therapy for genetic diseases. We are developing manufacturing processes for lentiviral vectors that can be administered to the body utilizing our experience in AAV.