While a number of companies have dabbled in this space, the following players are facilitating the development of iPS cell therapies: Cellular Dynamics International (CDI), RIKEN, Cynata Therapeutics, and Astellas (previously Ocata Therapeutics).

While each iPS cell therapy group is considered in detail below, Cellular Dynamics International (CDI) is featured first, because it dominates the iPSC industry. CDI also recently split into two business units, a Life Science Unit and a Therapeutics Unit, demonstrating a commercial strategy for its iPS cell therapy development.

Cellular Dynamics International (CDI) is headquartered in Madison, Wisconsin, although it provides technical support and sales information from both the United States and Japan. CDI was founded in 2004 and listed on NASDAQ in July 2013. The company had global revenues of $16.7 million in 2014 and currently has 150+ employees. It also has an extremely robust patent portfolio containing more than 800 patents, of which 130 pertain to iPSCs.

According to the company, CDI is the worlds largest producer of fully functional human cells derived from induced pluripotent stem (iPS) cells.[1] Their trademarked, iCell Cardiomyocytes, derived from iPSCs, are human cardiac cells used to aid drug discovery, improve the predictability of a drugs worth, and screen for toxicity. In addition, CDI provides: iCell Endothelial Cells for use in vascular-targeted drug discovery and tissue regeneration, iCell Hepatocytes, and iCell Neurons for pre-clinical drug discovery, toxicity testing, disease prediction, and cellular research.[2] As such, CDIs main role with regard to iPCS therapy development is the production of industrial-scale, clinical-grade iPSCs.

As mentioned previously, induced pluripotent stem cells were first produced in 2006 from mouse cells and in 2007 from human cells, by Shinya Yamanaka at Kyoto University,[3] who also won the Nobel Prize in Medicine or Physiology for his work on iPSCs.[4] Yamanaka has ties toCellular Dynamics International as a member of the scientific advisory board of iPS Academia Japan.

IPS Academia Japan was originally established to manage the patents and technology of Yamanakas work, and is now the distributor of several of Cellular Dynamics products, including iCell Neurons, iCell Cardiomyocytes, and iCell Endothelial Cells.[5] Importantly, in 2010 Cellular Dynamics became the first foreign company to be granted rights to use Yamanakas iPSC patent portfolio.Not only has CDI licensed rights to Yamanakas patents, but it also has a license to use Otsu, Japan-based Takara Bios RetroNectin product, which it uses as a tool to produce its iCell and MyCell products.[6] Through its licenses and intellectual property, CDI currently uses induced pluripotent stem cells to produce human heart cells (cardiomyocytes), brain cells (neurons), blood vessel cells (endothelial cells), and liver cells (hepatocytes), manufacturing them in high quantity, quality, and purity.

These human cells produced by the company are used for both in vitro and in vivo applications that range from basic and applied research to drug discovery research that includes target identification and validation, toxicity testing, safety and efficacy testing, and more. As such, CDI has emerged as a global leader with the ability to generate iPSCs that have the potential to be used for a wide range of research and possibly therapeutic purposes.

In a landmark event with the iPSC market, the company had an initial public offering (IPO) in July of 2013, in which it sold 38,460,000 shares of common stock to the public at $12.00 per share, to raise proceeds of approximately $43 million.[7] This event secured the companys position as the global leader in producing high-quality human iPSCs and differentiated cells in industrial quantities.

In addition, in March of 2013, Celullar Dynamics International and the Coriell Institute for Medical Research announced receiving multi-million dollars grants from the California Institute for Regenerative Medicine (CIRM) for the creation of iPSC lines from 3,000 healthy and diseased donors, a result that will create the worlds largest human iPSC bank.

Not surprisingly, Cellular Dynamics International has continued its innovation, announcing in February of 2015 that it would be manufacturing cGMP HLA Superdonor stem cell lines that will support cellular therapy applications through genetic matching.[8] Currently, CDI has two HLA superdonor cell lines that provide a partial HLA match to approximately 19% of the population within the U.S., and it aims to expand its master stem cell bank by collecting more donor cell lines that will cover 95% of the U.S. population.[9]

The HLA superdonor cell lines were manufactured using blood samples, and used to produce pluripotent iPSC lines, giving the cells the capacity to differentiate into nearly any cell within the human body.

CDI also leads the iPSC market in terms of supporting drug development and discovery. For example, CDIs MyCell products are created using custom iPSC reprogramming and differentiation methods, thereby providing biologically relevant human cells from patients with unique disease-associated genotypes and phenotypes.[10] The companys iCell and MyCell cells can also be adapted to screening platforms and are matched to function with common readout technologies.[11] CDIs products are also used for high-throughput screening,[12] and have been used as supporting data for Investigational New Drug (IND) applications submitted to the Federal Drug Administration (FDA).[13]

On March 30, 2015, Fujifilm Holdings Corporation announced that it was acquiring CDI, in which Fujifilm will acquire CDI through all-cash offer followed by a second step merger. Specifically, Fujifilm will acquire all issued and outstanding shares of CDIs common stock for $16.5 per share or approximately $ 307 million, after which CDI will continue to run its operations in Madison, Wisconsin, and Novato, California as a consolidated subsidiary of Fujifilm.[14]

CDIs technology platform enables the production of high-quality fully functioning iPSCs (and other human cells) on an industrial scale, while Fujifilm has developed highly-biocompatible recombinant peptidesthat can be shaped into a variety of forms for use as a cellular scaffoldin regenerative medicinewhen used in conjunction with CDIs products.[15] Fujifilm has been strengthening its presence in the regenerative medicine field over several years, including by acquiring a majority of shares of Japan Tissue Engineering Co. in December 2014, so while the acquisition was unexpected, it as not fully suprising.

In summary, the acquisition of CDI will allow Fujifilm to gaindominance in the areaof iPS cell-based drug discovery services and will position it to strategically combine CDIs iPS cell technologywithFujifilms expertise in material science and engineering systems, creating a powerhouse within the iPSC market. It is yet to be seen whether Fujifilm will try to commercialize CDIs iPS cell production technologies by making the cells available for clinical use or whether they will choose to focus their attention on iPS cell-based drug discovery services.

In November 2015 Astellas Pharma announced it was acquiring Ocata Therapeutics for $379M. Ocata Therapeutics is a biotechnology company that specializes in the development of cellular therapies, using both adult and human embryonic stem cells to develop patient-specific therapies. The companys main laboratory and GMP facility is in Marlborough, Massachusetts, and its corporate offices are in Santa Monica, California.

When a number of private companies began to explore the possibility of using artificially re-manufactured iPSCs for therapeutic purposes, one such company that was ready to capitalize on the breakthrough technology was Ocata Therapeutics (at the time called Advanced Cell Technology or ACT). In 2010, the company announced that it had discovered several problematic issues while conducting experiments for the purpose of applying for U.S. Food and Drug Administration approval to use iPSCs in therapeutic applications. Concerns such as premature cell death, mutation into cancer cells, and low proliferation rates were some of the problems that surfaced. [16]

As a result, the company has since shifted its induced pluripotent stem cell approach to producingiPS cell-derived human platelets, as one of the benefits of a platelet-based product is that platelets do not contain nuclei, and therefore, cannot divide or carry genetic information. Although nothing is completely safe, iPS cell-derived platelets are likely to be much safer than other iPSC therapies, in which uncontrolled proliferation is a major concern.

While the companys Induced Pluripotent Stem Cell-Derived Human Platelet Program received a great deal of media coverage in late 2012, including being awarded the December 2012 honor of being named one of the 10 Ideas that Will Shape the Yearby New Scientist Magazine,[17] unfortunately the company did not succeed in moving the concept through to clinical testing in 2013.

Nonetheless, in a November 2015 presentation by Astellas President and CEO, Yoshihiko Hatanaka, he indicated that the company will aim to develop an Ophthalmic Disease Cell Therapy Franchise based around its embryonic stem cells (ESCs) and induced pluripotent stem cell (iPS cells) technology. [18]

On June 22, 2016, RIKEN announced that it is resuming its retinal induced pluripotent stem cell (iPSC) study in partnership with Kyoto University.

2013 was the first time in which clinical research involving transplant of iPSCs into humans was initiated, led by Masayo Takahashi of the RIKEN Center for Developmental Biology (CDB)in Kobe, Japan. Dr. Takahashi and her team wereinvestigating the safety of iPSC-derived cell sheets in patients with wet-type age-related macular degeneration. Althoughthe trial was initiated in 2013 and production of iPSCs from patients began at that time, it was not until August of 2014 that the first patient, a Japanese woman, was implanted with retinal tissue generated using iPSCs derived from her own skin cells.

A team of three eye specialists, led by Yasuo Kurimoto of the Kobe City Medical Center General Hospital, implanted a 1.3 by 3.0mm sheet of iPSC-derived retinal pigment epithelium cells into the patients retina.[19]Unfortunately, the study was suspended in 2015 due to safety concerns. As the lab prepared to treat the second trial participant, Yamanakas team identified two small genetic changes in the patients iPSCs and the retinal pigment epithelium (RPE) cells derived from them. Therefore, it is major news that theRIKEN Institute will now be resuming the worlds first clinical study involving the use of iPSC-derived cells in humans.

According to the Japan Times, this attempt at the clinical studywill involve allogeneic rather than autologous iPSC-derived cells for purposes of cost and time efficiency.Specifically,the researchers will be developing retinal tissues from iPS cells supplied by Kyoto Universitys Center for iPS Cell Research and Application, an institution headed by Nobel prize winner Shinya Yamanaka. To learn about this announcement, view this article fromAsahi Shimbun, aTokyo- based newspaper.

Australian stem cell company Cynata Therapeutics (ASX:CYP) is taking a unique approach. It is creating allogeneic iPS cell derived mesenchyal stem cell (MSCs).Cynatas Cymerus technology utilizes iPSCs originating from an adult donor as the starting material for generating mesenchymoangioblasts (MCAs), and subsequently, for manufacturing clinical-gradeMSCs.

One of the key inventors of the approach is Igor Slukvin, who has released more than 70 publications about stem cell topics, including the landmark article in Cell describing the now patented Cymerus technique. Dr. Slukvins co-inventor is James Thomson, the first person to isolate an embryonic stem cell (ESC) and one of the first people to create a human-induced, pluripotent stem cell (hiPSC).

Recently, Cynata received advice from the UK Medicines and Healthcare products Regulatory Agency (MHRA) that its Phase I clinical trial application has been approved, titledAn Open-Label Phase 1 Study to Investigate the Safety and Efficacy of CYP-001 for the Treatment of Adults With Steroid-Resistant Acute Graft Versus Host Disease. It will be the worlds first clinical trial involving a therapeutic product derived from allogeneic (unrelated to the patient) induced pluripotent stem cells (iPSCs).

Participants for Cynatas upcoming Phase I clinical trial will be adults who have undergone an allogeneic haematopoietic stem cell transplant (HSCT) to treat a haematological disorder and subsequently been diagnosed with steroid-resistant Grade II-IV GvHD.The primary objective of the trial is to assess safety and tolerability, while the secondary objective is to evaluate the efficacy of two infusions of CYP-001 in adults with steroid-resistant GvHD.

There are four key advantages of Cynatas proprietary Cymerus MSC manufacturing platform, as described below.

Unlimited Quantities Cynatas Cymerus technology utilizes iPSCs originating from an adult donor as the starting material for generating mesenchymoangioblasts (MCAs), and subsequently, for manufacturing clinical-gradeMSCs. According to Cynatas Executive Chairman Stewart Washer who was recently interviewed by The Life Sciences Report, The Cymerus technology gets around the loss of potency with the unlimited iPS cellor induced pluripotent stem cellwhich is basically immortal.

Uniform Batches Because the proprietary Cymerus technology allows nearly unlimited production of MSCs from a single iPSC donor, there is batch-to-batch uniformity. Utilizing a consistent starting material allows for a standardized cell manufacturing process and a consistent cell therapy product.

Single Donor As described previously, Cynatas Cymerus technology creates iPSC-derived mesenchymoangioblasts (MCAs), which are differentiated into MSCs. Unlike other companies involved with MSC manufacturing, Cynata does not require a constant stream of new donors in order to source fresh stem cells for its cell manufacturing process, nor does it require the massive expansion of MSCs necessitated by reliance on freshly isolated donations.

Economic Manufacture at Commercial Scale (Low Cost) Finally, Cynata has achieved a cost-savings advantage through its uniqueapproach to MSCmanufacturing. Its proprietary Cymerus technology addresses a critical shortcoming in existing methods of production of MSCs for therapeutic use, which is the ability to achieve economic manufacture at commercial scale.

Footnotes [1] CellularDynamics.com (2014). About CDI. Available at: http://www.cellulardynamics.com/about/index.html. Web. 1 Apr. 2015. [2] Ibid. [3] Takahashi K, Yamanaka S (August 2006).Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell126(4): 66376. [4] 2012 Nobel Prize in Physiology or Medicine Press Release. Nobelprize.org. Nobel Media AB 2013. Web. 7 Feb 2014. Available at: http://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/press.html. Web. 1 Apr. 2015. [5] Striklin, D (Jan 13, 2014). Three Companies Banking on Regenerative Medicine. Wall Street Cheat Sheet. Retrieved Feb 1, 2014 from, http://wallstcheatsheet.com/stocks/3-companies-banking-on-regenerative-medicine.html/?a=viewall. [6] Striklin, D (2014). Three Companies Banking on Regenerative Medicine. Wall Street Cheat Sheet [Online]. Available at: http://wallstcheatsheet.com/stocks/3-companies-banking-on-regenerative-medicine.html/?a=viewall. Web. 1 Apr. 2015. [7] Cellular Dynamics International (July 30, 2013). Cellular Dynamics International Announces Closing of Initial Public Offering [Press Release]. Retrieved from http://www.cellulardynamics.com/news/pr/2013_07_30.html. [8] Investors.cellulardynamics.com,. Cellular Dynamics Manufactures Cgmp HLA Superdonor Stem Cell Lines To Enable Cell Therapy With Genetic Matching (NASDAQ:ICEL). N.p., 2015. Web. 7 Mar. 2015. [9] Ibid. [10] Cellulardynamics.com,. Cellular Dynamics | Mycell Products. N.p., 2015. Web. 7 Mar. 2015. [11]Sirenko, O. et al. Multiparameter In Vitro Assessment Of Compound Effects On Cardiomyocyte Physiology Using Ipsc Cells.Journal of Biomolecular Screening18.1 (2012): 39-53. Web. 7 Mar. 2015. [12] Sciencedirect.com,. Prevention Of -Amyloid Induced Toxicity In Human Ips Cell-Derived Neurons By Inhibition Of Cyclin-Dependent Kinases And Associated Cell Cycle Events. N.p., 2015. Web. 7 Mar. 2015. [13] Sciencedirect.com,. HER2-Targeted Liposomal Doxorubicin Displays Enhanced Anti-Tumorigenic Effects Without Associated Cardiotoxicity. N.p., 2015. Web. 7 Mar. 2015. [14] Cellular Dynamics International, Inc. Fujifilm Holdings To Acquire Cellular Dynamics International, Inc.. GlobeNewswire News Room. N.p., 2015. Web. 7 Apr. 2015. [15] Ibid. [16] Advanced Cell Technologies (Feb 11, 2011). Advanced Cell and Colleagues Report Therapeutic Cells Derived From iPS Cells Display Early Aging [Press Release]. Available at: http://www.advancedcell.com/news-and-media/press-releases/advanced-cell-and-colleagues-report-therapeutic-cells-derived-from-ips-cells-display-early-aging/. [17] Advanced Cell Technology (Dec 20, 2012). New Scientist Magazine Selects ACTs Induced Pluripotent Stem (iPS) Cell-Derived Human Platelet Program As One of 10 Ideas That Will Shape The Year [Press Release]. Available at: http://articles.latimes.com/2009/mar/06/science/sci-stemcell6. Web. 9 Apr. 2015. [18] Astellas Pharma (2015). Acquisition of Ocata Therapeutics New Step Forward in Ophthalmology with Cell Therapy Approach. Available at: https://www.astellas.com/en/corporate/news/pdf/151110_2_Eg.pdf. Web. 29 Jan. 2017. [19]Cyranoski, David. Japanese Woman Is First Recipient Of Next-Generation Stem Cells. Nature (2014): n. pag. Web. 6 Mar. 2015.

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