Japan: The Latest Therapeutic Applications in Induced Pluripotent Stem Cell (iPSC) Technology


Toshio Fujimoto, MBA, MD of Japan’s Shonan Health Innovation Park looks at how a technology developed in Japan over a decade ago is poised to drive major medical advances and new treatments.


Here’s what we know today and what we’ll need to do tomorrow to benefit from the promises of iPCS.


Induced pluripotent stem cell (iPSC) was introduced by a Japanese researcher, Dr Shinya Yamanaka, in 2006. IPSC offers infinite possibilities for drug discovery and cell therapeutics. But it comes with potential challenges as well. In this article, the current status of IPSC clinical application is summarized to offer an overview of what is necessary to accelerate this Japan-originated technology to the market for patient benefit.


Technology developed in Japan 14 years ago has since been adopted by over 200 different academic institutes and companies that are currently working on products using iPSC technology


There are two main ways that iPSC technology translates into clinical applications: iPCS-based cell therapeutics (clinical Rx) and iPSC for drug screening and research (clinical modeling).


We at Shonan Health Innovation Park recently completed a landscape analysis of iPSC around the world and found that that new technology developed in Japan 14 years ago has since been adopted by over 200 different academic institutes and companies that are currently working on products using iPSC technology. This figure illustrates the developmental stages of the research groups and companies worldwide, classified by the therapeutic areas, development stages, and the purposes (Clinical Rx vs. Clinical Modeling). The research and development are centered upon the areas of high unmet needs where the protocols for tissue/organ differentiation are established. Characteristic features in each area are described below.

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  • Neurology: There are many rare neurological conditions caused by one or more gene mutations, for which iPSCs can be used. The lack of effective animal models in many neurological diseases has also put more attention to the new approach for drug discovery. Many iPSC-driven clinical trials are ongoing, both clinical modelling and cell therapeutics, including direct injection of iPSC neural cells into the brain for patients with Parkinson’s disease. Researchers are particularly focused on Parkinson’s disease, ALS, neurodegenerative disease, and Huntington disease. Challenges in this space include the incorporation of aging into neuronal models, and automation of phenotypic assays to support quantitative drug efficacy and toxicity.


  • Ophthalmology: The retina (especially retinal pigment epithelium) is a promising area for iPSC research because of its unique features, including easy monitoring of grafted tissue, relatively easy access through surgery, comparatively lower rates of immunogenicity, and comparatively faster restoration of synaptic connectivity. Current clinical application is focused on age-related macular degeneration, Stargardt disease, and retinitis pigmentosa.


  • Cardiology: Heart tissue is one of the least regenerative in the body, and function recovery is not expected after injury, and stem cell transplant has been investigated for the treatment of heart failure extensively. iPSC-derived cardiomyocytes are being transplanted by direct injection into the heart tissue or applied with sheet-based or scaffolding-based engineered tissue. Drug screening models are also used relatively frequently in the cardiology space. Yet the feasibility of producing human cardiomyocytes for clinical use may be hampered by the presence of heterogeneous cell populations, including undifferentiated iPSCs or noncardiac cells eliciting off-target outcomes.


  • Oncology: While some products of patient-derived CAR-T cells are already on the market in oncology, many companies are applying iPSC technology to develop “off-the-shelf” treatments using allogeneic stem cells. Off-the-shelf is especially important for patients with cancer because the patients may not allow time to harvest cells, engineer genetically, proliferate, and re-introduce the cells. iPSC technology allows for easy genomic modifications to produce CAR-T/NK cells with improved anti-tumour activities. Several clinical trials are currently underway for a variety of tumour types, both for liquid and solid tumours.


How do we bring iPSC to scale in a cost-effective manner? It is important to note that academia is playing an important role in the exploratory clinical investigations for cell therapeutics. The manufacturing process of iPSC is not robust enough and it requires skilled technicians for manufacturing operations in limited academic institutions. Therefore, only these academic institution are able to lead clinical investigation in a pilot scale with a relatively small number of patients. More efforts for process development and ultimately automation of cell manufacturing need to be established by pharmaceutical industries, which is the bottleneck of iPSC-based cell therapeutics.


iPSC-based drug screening has shown promising results in drug discovery and is being used by an increasing number of pharmaceutical companies. This approach is especially applicable in diseases with a small number of mutations. Further collaboration between industry and academia is expected to establish standard models in many diseases, and should be successful in collecting a wide range of patient cells to apply this method for diseases with heterogeneous genomic backgrounds.


Clinical applications of iPSC technology are in advanced development by many companies and universities around the world. So what does the future hold? The winners will be the ones who can address the issues of safety, quality, and scale by accelerating the translation and transition of theories and technologies in modelling and manufacturing from academia to industry by intense collaboration beyond countries, and create de-facto global standards for this emerging innovation.


Image: Retinal pigment epithelium cells by National Institutes of Health (NIH)

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