DB: Thank you, Dr Kawada, for joining me. You have just published a very exciting paper looking to use iPSC-derived cells to repair peripheral nerve damage. But before we get into the science, could you tell me about Jiksak Bioengineering and the collaborations that led to this paper.
JK: Thank you, Duncan, Jiksak Bioengineering was founded in 2017. The company focuses on neuromuscular diseases and develops therapeutic methods with the goal of creating a world where the recovery of motor function can be achieved. Initially the aim of the company was to develop our nerve organoid technology with the goals of creating nerves similar to those of the human body, and to reproduce nerves with similar pathological conditions as seen in patients. This technology will be useful in the search for treatment methods for neuromuscular diseases. I knew Dr. Shibata, the co-researcher of this paper, who is affiliated with Niigata University and Keio University, before I established Jiksak Bioengineering. After I started Jiksak, we came up with the idea of the possibility of using nerve organoids, which resemble nerve tissue in the human body, for transplantation as a substitute for autologous nerves. This led to our joint research and finally the publication of this paper.
DB: That’s very helpful. Severe peripheral nerve damage can have many origins – severe accidents, falls, cut nerves but also medical conditions including diabetes and a range of autoimmune diseases. Could you summarize what progress has been made up to now, to find adequate treatments, and your motivation for this new iPSC-based research.
JK: The gold standard treatment for neurotmesis, the most serious form of nerve injury, where both the nerve and the nerve sheath are disrupted, is autologous nerve transplantation. This treatment has excellent outcomes and versatility, but, it sacrifices the patient’s own nerve and there are challenges in terms of the complete restoration of motor function. Artificial nerve transplantation which overcomes the problem of losing the patient’s autologous nerve is a good option, but the length of artificial nerves available for transplantation are limited, and the therapeutic outcome is not as good as that of autologous transplantation. Recent studies have combined artificial nerve products with Schwann cells and stem cell systems to enhance the effectiveness of nerve regeneration. We hope to create allogeneic products that could replace autologous transplants by using nerve organoids that closely resemble the structure of living neural tissue. This can be done by manufacturing nerve organoids from iPSC master cell stocks. We believe our technology can ensure the consistent manufacture and supply, as well as the high quality and performance of the allogeneic product.
DB: And what is really novel in your paper is the use of human iPSC derived axoCells Sensory Neurons from Axol Bioscience, within a microfluidic device which is then transplanted. Could you tell me more about the technical challenges you faced with this work?
JK: First, we had to consider the methods to use to implant the nerve organoids. We also had to determine how to extract the nerve organoids, which are cultured in a thin microfluidic device about 1 mm in diameter, with minimum damage. Because the cultured nerve organoid tissue is capable of self-assembly into axon bundles and is strong enough to be handled with tweezers, we were able to place several bundles together in a silicone tube filled with collagen gel, after much trial and error. We would not have been able to prepare and analyze the animal model of our nerve organoids integrated into silicone tube implant without the support of our collaborators. I would like to express my gratitude to Dr. Shibata and the other professors who were involved in this project. Our collaborator, Dr. Shibata, and his team worked hard to evaluate the regeneration mechanisms from various perspectives and quantitatively analyzed the data.
DB: And of course, the excitement here is that you saw therapeutic improvements post-transplant, both functionally and histologically. Also, this occurred without the need for immunosuppression. This must have been thrilling for your group.
JK: I was truly amazed. In addition to histological recovery, including axonal regeneration, myelination, and angiogenesis, the sensory and motor functions were restored as well, as demonstrated by a reduction in self-inflicted injury in the model animals. Even though our nerve organoid is not myelinated by Schwann cells, it is still capable of promoting nerve regeneration mediated by T cells and macrophages. With our nerve organoid microfluidic device, the cell nucleus portion of the cell spheroid can be separated from the axon bundle. The cell nuclei of the artificial nerve was physically removed during the manufacturing process so that our allograft product only encompasses the nerve axons of the nerve organoid. Excluding the cell nucleus from the beginning of allograft production is important not only in terms of reducing the risk of tumorigenesis, but also remove the need to use immunosuppression drugs after transplantation.
DB: And a look to the future? Where is your research going next?
JK: We are aiming to commercialize the allograft product. We are currently working with a joint research partner on a large-scale animal study. Even though our strength is in our technology, being a small venture business in Japan there is a limit to what we can do alone so we are seeking investment and collaboration with other companies and research institutions to bring the product to market.
Duncan Borthwick PhD is Head of Sales and Marketing at Axol and interviewed Jiro Kawada, Ph.D. Co-CEO Jiksak Bioengineering.
This paper used the following products from Axol Bioscience:
- ax0555: axoCells Human iPSC-Derived Sensory Neuron Progenitors
