iPS Cell Therapy: Is Japan the Market Leader?

An induced pluripotent stem cell (iPS cell) is a type of pluripotent stem cell that has the capacity to divide indefinitely and create any cell found within the three germ layers of an organism.

These layers include the ectoderm (cells giving rise to the skin and nervous system), endoderm (cells forming gastrointestinal and respiratory tracts, endocrine gland, liver, and pancreas), and mesoderm (cells forming bones, cartilage, most of the circulatory system, muscles, connective tissues, and other related tissues.).

iPS cells have significant potential for therapeutic applications. For autologous applications, the cells are extracted from the patient’s own body, making them genetically identical to the patient and eliminating the issues associated with tissue matching and tissue rejection.

iPS Cell Applications

iPS cells have the potential to be used to treat a wide range of diseases, including diabetes, heart diseases, autoimmune diseases, and neural complications, such as Parkinson’s disease, Alzheimer’s disease.

Importantly, iPS cells are being explored for their use in:

• Cell therapy applications
• Drug development and discovery
• Toxicology testing
• Disease modelling
• Personalized medicine

iPS Cells Discovery

Japan has a unique affection for iPS cells, as the cells were originally discovered by the Japanese scientist, Shinya Yamanaka of Kyoto University.  Mr. Yamanaka was awarded the Nobel Prize in Physiology or Medicine for 2012, an honor shared jointly with John Gurdon, for the discovery that mature cells can be reprogrammed to become pluripotent.

Masayo Takahashi of the RIKEN Center for Developmental Biology in Kobe, Japan—who led the world’s first clinical research using an iPSC-derived product in humans—was chosen by the journal Nature as one of five scientists to watch in 2014.

Japan also made early strides into the market for iPSC-derived research products. In 2009, ReproCELL was established as a venture company originating from the University of Tokyo and Kyoto University. It became the first company worldwide to launch an iPSC-derived research product. Its first product was a human iPSC-derived cardiomyocyte, sold under the brand name ReproCardio.

If that was not enough, Japan’s Education Ministry allocated an astounding 110 billion yen ($1.13 billion) to promote induced pluripotent stem cell research over a 10 year period. The Japanese parliament evaluated bills that would “speed the approval process and ensure the safety of such treatments” and passed a law calling for Japan to make regenerative medical treatments like iPSC technology available for its citizens “ahead of the rest of the world.”

iPS Cells in Japan

In recent years, Japan has accelerated its position as a hub for regenerative medicine research. This has been driven by support from Prime Minister Shinzo Abe, who has identified regenerative medicine and cellular therapy as key to the Japan’s strategy to drive economic growth.

The Prime Minister encouraged a wide range of collaborations between private industry and academic partners through an innovative legal framework. He also initiated campaigns to drive technological advances in drugs and devices by connecting private companies with public funding sources.

The result has been progress in both basic and applied research involving induced pluripotent stem cells (iPS cells) and related stem cell technologies.

Japan’s First Clinical Study with an iPSC-derived Therapeutic Product

2013 was a landmark year in Japan, because it saw the first cellular therapy involving transplant of iPS cells into humans initiated at the RIKEN Center in Kobe, Japan. Led by Masayo Takahashi of the RIKEN Center for Developmental Biology (CDB). Dr. Takahashi and her team investigated the safety of iPSC-derived cell sheets in patients with wet-type age-related macular degeneration.

To speed things along, RIKEN did not seek permission for a clinical trial involving iPS cells, but instead applied for a type of pretrial clinical research allowed under Japanese regulations. The RIKEN Center is Japan’s largest, most comprehensive research institution. It is backed by both Japan’s Health Ministry and its government.

This “pretrial clinical research” allowed the RIKEN research team to test the use of iPS cells for the treatment of AMD on a very small scale in a handful of patients. Unfortunately, the study was suspended in 2015 due to safety concerns. As the lab prepared to treat the second trial participant, Yamanaka’s team identified two small genetic changes in the patient’s iPSCs and the retinal pigment epithelium (RPE) cells derived from them.

iPS Cell Therapy

In June 2016 RIKEN Institute resumed this clinical study involving the use of iPSC-derived cells in humans. This resumed attempt at the clinical study switched to using allogeneic rather than autologous iPSC-derived cells, because of the cost and time efficiencies associated with allogeneic cells. The iPS cells for this study were supplied by Kyoto University’s Center for iPS Cell Research and Application, an institution headed by Nobel prize winner Shinya Yamanaka.

Within the U.S., the National Institutes of Health (NIH) initiated its first clinical trial of an iPSC-derived therapeutic in December 2019. The goal of this trial is to restore dying cells of the retina. The Phase I/IIa clinical trial involves 12 patients with advanced-stage geographic atrophy who received an iPSC-derived retinal pigment epithelial (RPE) implant into a single eye.

This trial is supported by the Ocular and Stem Cell Translational Research Section of the National Eye Institute (NEI). The NEI is part of the NIH.

Cynata Therapeutics and Fujifilm

In another world-first, Cynata Therapeutics (ASX:CYP) received approval in September 2016 to launch the world’s first formal clinical trial with an allogeneic iPSC-derived cell product. In this historic trial, the Australian regenerative medicine company tested an iPS cell-derived mesenchymal stem cell (MSC) product for the treatment of Graft-vs-Host-Disease (GvHD).

Since this study involved centers in the UK and Australia, how was it relevant to Japan? Simple, the Japanese conglomerate Fujifilm was involved with it.

Headquartered in Tokyo, Fujifilm is one of the largest players in regenerative medicine field and has invested significantly into stem cells through their acquisition of Cellular Dynamics International (CDI). Fujifilm also invested in Japan Tissue Engineering Co. Ltd. (J-Tec), giving it a broad base in regenerative medicine across multiple therapeutic areas.

iPS Cell Technology

For a young company like Cynata, having validation from an industry giant like Fujifilm was a major boost. As stated by Cynata CEO, Dr. Ross Macdonald, “The decision by Fujifilm confirms that our technology is very exciting in their eyes. It is a useful yardstick for other investors as well. Of course, the effect of the relationship with Fujifilm on our balance sheet is also important.”

Cynata was the first to scale-up manufacture of an allogeneic cGMP iPS cell line. It sourced the cell line from Cellular Dynamics International (CDI) when CDI was still an independent company listed on NASDAQ. In April 2015, CDI was wholly acquired by Fujifilm, who as mentioned, is a major shareholder in Cynata and its strategic partner for GvHD.

Today, Cynata is advancing its iPSC-derived MSCs into Phase 2 trials for complications associated with COVID-19, as well as GvHD and critical limb ischemia (CLI). It is also undertaking an impressive Phase 3 trial that will utilize Cynata’s iPSC-derived mesenchymal stem cell (MSC) product, CYP-004, in 440 patients with osteoarthritis (OA).

Although clinical trials are being undertaken across multiple geographies, methods for commercializing iPS cells are still being explored and studies investigating this cell type remain low in number.

iPS Cell Advantages and Disadvantages

Clearly, Japan is a market leader in iPS cell technologies and therapies. However, progress with stem cells has not been without setbacks within Japan, including a scandal at the RIKEN Institute that involved falsely manipulated research findings and a hold on the first clinical study involving transplant of an iPS cell product into humans.

Thankfully, Japan has emerged from these troubles to become the nation most aggressively pursuing the development of iPSC technologies.

Although there is growing evidence to support the safety of iPS cells within cell therapy applications, some people remain concerned that patients who receive implants of iPS derived cells might be at risk of cancer. This is because there is genetic manipulation is required to create the cell type.

Nonetheless, since the discovery of iPSC technology 15 years ago, significant progress has been made in stem cell biology and regenerative medicine. New pathological mechanisms have been identified, new drugs identified by iPSC screens are in the pipeline, and 54 clinical trials are underway. Most of these trials involve the creation and evaluation of iPSC lines for clinical purposes, not the transplant of iPSCs into humans.

Finally, iPSCs can be used to explore the causes of disease onset and progression, create and test new drugs and therapies, and potentially, treat previously incurable diseases.

To learn more, view the “Global Induced Pluripotent Stem Cell (iPSC) Industry Report 2021.”