Cell therapy for cardiac conditions: an interview with Takehiko Kaneko
We spoke to Takehiko Kaneko, Chief Medical Officer of Heartseed Inc. (Japan), about cardiac regenerative medicine. Kaneko explained Heartseed’s mission and gave an insight into the current trends in the field of cardiac regenerative medicine. Additionally, Kaneko discussed some of the most important factors when it comes to for efficient cardiomyocyte differentiation and shared how spheroids are used during transplantation of cardiomyocytes.
Please introduce yourself and tell us how you became involved with Heartseed Inc.
I’m the Head of R&D and Chief Medical Officer at Heartseed Inc. Heartseed develops iPSC-derived cardiomyocytes to treat heart disease. I joined in June 2020, and before that spent 5 years as a physician and 16 years in the pharmaceutical and biotech industry, focusing the last 7 years on cell-therapy.
When I was a medical school student, I saw a news program that reported cardiomyocytes were regenerated from mesenchymal stem cells. That research was done by Professor Fukuda’s laboratory at my medical school. In 2015, Professor Keiichi Fukuda established Heartseed Inc. to develop heart regeneration therapy. In the same year, I started at SanBio, a cell therapy company, after I’d worked for Bristol Myers Squibb, Pfizer and Novartis.
At SanBio, I was in charge of development. We initiated a new multiregional clinical study for mesenchymal stem cell products in the central nervous system, and completed it successfully with good efficacy and safety results. Based on the study results, we got a CIRM grant, RMAT designation in the United States and Sakigake designation in Japan.
In a cell therapy area, companies started to develop iPSC-derived products, but only some overcome problems in the research phase such as tumorigenicity, product quality and process development. One of those is Heartseed. Fukuda shared his progress and vision in iPSC therapy with me; this really excited me and I decided to join Heartseed.
Heartseed’s mission is to enable the treatment of heart disease through regenerative medicine, what is the motivation behind this?
Heart disease is a major cause of death in many countries including the United States and Japan. The most common type of heart disease is coronary artery disease, which affects the blood flow to the heart and is at the root of heart failure.
Over 65 million patients are suffering from heart failure worldwide and the number is on the rise. Current drug therapies are used to reduce the burden on the heart but do not address the root cause of the disease: loss of cardiomyocytes.
Heart transplants and ventricular assistive devices (VADs) are used to give significant improvement for severe heart failure. However, recipients are very limited, and the cost of the operation and maintenance is quite expensive. There is therefore a worldwide unmet clinical need for new therapeutic strategies for heart failure. Fukuda has seen many heart failure patients and founded Heartseed, making an unwavering commitment to saving patients. All Heartseed members are working for the same mission: “Open the door to the treatment of heart disease through regenerative medicine”.
What are the current trends and innovations in cardiac regenerative medicine that you are excited about?
Current trends of cardiac regenerative medicine are therapies with a paracrine effect. Skeletal myoblasts, bone marrow mononuclear cells or mesenchymal stem cells are used for many projects for heart regeneration, as they can release trophic factors. Products with this mechanism showed efficacy and tolerability in clinical studies, but the results of clinical studies haven’t had an impact on treatment guidelines for heart failure. So, we still need an innovative treatment. Our remuscularization approach will be the answer for the question.
What is ‘remuscularization’ and how is it achieved?
Remuscularization is our innovative treatment concept that transplants and replenishes regenerated cardiomyocytes. In this concept, cardiomyocytes should engraft in a patient’s myocardium long-term, electrically couple with the patient’s heart and contribute to direct contractile force. We developed technologies that are necessary to achieve remuscularization.
The technologies have two elements. The first element is differentiation. After we generated iPSCs, they will be differentiated into cardiomyocytes. Our technology is able to make ventricular specific cardiomyocytes. Among the cardiomyocytes, those in the sinoatrial/atrioventricular nodes, atrial cardiomyocytes and ventricular cardiomyocytes are different in their characteristics, such as ion channel expressions and electronic activity. Ventricular cardiomyocytes rarely cause arrhythmia, since their idioventricular rhythm is slower than others. Therefore, ventricular cardiomyocytes are necessary for remuscularization strategy.
The second element is purification. Usually, there are residual undifferentiated iPSCs when people try to differentiate iPSCs into target cells. Residual iPSCs cause many problems; they can be differentiated into non-target cells and at the worst case, they will form teratoma. For clinical use, residual iPSCs should be eliminated while ventricular cardiomyocytes grow. Heartseed developed a special medium, and achieved both below 0.001% detection of residual iPSCs and 99%+ purity of ventricular cardiomyocytes. Just changing cell culture medium enables us to eliminate most of the non-cardiomyocytes and iPSCs. Since we have successfully developed two key technologies, our remuscularization therapy has become realized.
What are the most important factors for efficient cardiomyocyte differentiation and how can they be accomplished?
Heartseed has a patented method for purification which comes from the difference of metabolism between iPSCs and cardiomyocytes. Glucose and glutamine are two key energy sources, and both iPSCs and cardiomyocytes cannot survive without them. Only cardiomyocytes can survive in a medium without glutamine and glucose when lactate is supplemented. Based on this finding, we developed an innovative medium to only grow cardiomyocytes by adding lactate, but to terminate iPSCs and non-cardiomyocytes by removing glutamine and glucose from the medium. Furthermore, unsuitable immature cardiomyocytes can also be removed by this method, so we can obtain appropriately-matured cardiomyocytes. This method increases efficacy of our cardiomyocytes and minimizes the risk of teratoma formation.
How are cardiomyocyte spheroids utilized during transplantation of cardiomyocytes and how does this aid the process?
In past articles in scientific journals, researchers reported that engraftment rates of cardiomyocytes were low after single-cell transplantation. Heartseed choose spheroid transplantation to increase retention rate. A spheroid has 100-1000 cardiomyocytes. Cardiomyocyte spheroid transplantation has a higher retention rate than transplantation of single cell cardiomyocytes [1]. In addition, we created a special needle to transplant spheroids. The needle has multiple side holes for safe and effective spheroid delivery. A typical injection needle has a knife-like edge at the tip to insert to the skin smoothly. Our special needle doesn’t have such an edge and its tip is dull; thus, it can minimize the bleeding from the injected site. Those technologies contribute to a high retention rate and safe transplantation.
How do you expect cardiac regenerative medicine to develop over the next few years?
Most cardiac regenerative medicines have been focusing on the patients with heart failure or ischemic heart disease. There are many incurable diseases in the cardiology area, and those rare diseases would become a target for cardiac regenerative medicine in the near future. Heartseed has already started R&D activities for cardiac rare diseases.
Autologous therapy is another topic for future regenerative medicine. While off-the shelf treatment is much easier in terms of business operations, autologous therapy is attractive for patients who have a concern for transient use of immunosuppressants, such as severe stage heart failure and autoimmune disease. Hurdles of autologous therapy are inefficiency of manufacturing iPSCs from patients’ blood and the variance of iPSC quality – in particular, differentiation efficiency into desired cells. Heartseed has the proprietary technology to address these issues, by co-transfecting H1foo. Akira Kunitomi reported in 2016 that H1foo induced efficiency in reprogramming for iPSC generation [2]. H1foo technology overcomes the hurdle of the autologous therapy, and increase yield of desired cells. It will open a door for personalized cardiomyocyte therapy.
References
- Tabei R, Kawaguchi S, Kanazawa H et al. Development of a transplant injection device for optimal distribution and retention of human induced pluripotent stem cell‒derived cardiomyocytes. J Heart Lung Transplant. 38(2):203-214 (2019)
- Kunitomi A, Yuasa S, Sugiyama F et al. H1foo Has a Pivotal Role in Qualifying Induced Pluripotent Stem Cells. Stem Cell Reports, 14;6(6):825-833 (2016)
Disclaimer
The opinions expressed in this interview are those of the interviewees and do not necessarily reflect the views of RegMedNet or Future Science Group.