November 1, 2016 (Vol. 36, No. 19)

CDI’s Stem Cells Are Advancing Basic Research and Supporting Clinical Development

Induced pluripotent stem cells (iPSCs) have emerged from the general stem cell controversies of the early 2000s to offer potential cures for significant degenerative diseases.

“Even one year ago, the understanding that this was possible wasn’t pervasive,” said biopharmaceutical professional Chris Parker. At the time this article was prepared, Parker was still executive vice president and chief business officer of iPSC manufacturer Cellular Dynamics International (CDI). The company’s acquisition by Fujifilm in May 2015 demonstrated that CDI and iPSCs had gained traction in the industry. Regenerative medicine, strongly supported by iPSCs, “now has high visibility in Japan,” Parker declared. “iPSCs are now mainstream therapeutic research tools.”

As evidence, he cited numerous examples of iPSC research applications, including studies of chemotherapy-induced neuropathy, development of multicellular body-on-a-chip models, drug screening for hepatitis B and C therapeutics, construction of engineered tissues, and iPSC repopulation of decellularized organs.

The Comprehensive In Vitro Proarrhythmia Assay (CiPA) consortium also is evaluating whether in vitro iPSC-based arrhythmia assays could replace dedicated (and expensive) studies of QT intervals. “This industry-government collaboration is generating data to reproduce the results of clinical trials,” explained Parker. “We anticipate a draft guidance from the FDA by the end of 2017.”

At CDI’s facilities in Madison, WI, researchers develop next-generation therapies and research tools based on human induced pluripotent stem cell technology.

Anticipating Users’ Needs

 “We are the world’s largest producer of iPSCs and their differentiated progeny. We commercialized the first human iPSC-derived model in December 2009, less than three years after the discovery of iPSCs,” said Emile F. Nuwaysir, Ph.D., CDI’s president and COO. “Now we produce 13 different categories of human cell types from iPSCs, each with more than 95% purity.”

A pioneer of iPSC manufacturing, CDI demonstrated as early as 2005 that terminal cells could be generated from embryonic stem cells in substantial quantities. Their availability in ever increasing quantities made it possible for iPSC-derived cells to be used first in drug discovery and toxicology testing and, more recently, in preclinical and pretherapeutic models. Today, CDI manufactures billions of iPSCs each day. “The science,” noted Parker, “has caught up to our manufacturing capabilities.”

CDI manufactures endoderm, mesoderm, and ectoderm cells—the three major developmental lineages that make up, respectively, the inner, middle, and outer layers of tissues during embryonic development. Specific CDI cell types include cardiomyocytes, cardiac progenitor cells, neurons, astrocytes, dopaminergic neurons, hepatocytes, hepatoblasts, skeletal myoblasts, endothelial cells, hematopoietic progenitor cells, and macrophages. Custom services include cell reprogramming, genetic engineering at the cellular level, and cell differentiation.

Importantly, CDI’s manufacturing method does not induce mutagenesis. Rather than using viral vectors to reprogram cells, the company utilizes episomal reprogramming (which harnesses circular DNA vectors to deliver pluripotency factors to somatic cells) to create iPSCs.

“Our method employs an episome that contains the transcription factors needed to drive the cell to pluripotency,” Dr. Nuwaysir explained. “That episome never integrates into the cell. Because there is no mutagenesis, you get a better research model—one that can be used for therapeutics.”

These cells, therefore, may be used in the clinic. “This method,” Dr. Nuwaysir insisted, “is becoming the standard for clinical-grade iPSCs.”

Expanding the Pipeline

CDI offers two brands of iPSC-derived cells: iCell® and MyCell®. “The iCell family of products is composed of terminally differentiated cells representing “typical” human biology,” said Parker. “They are derived from normal, healthy individuals.” iCell products have utility in discovery and regenerative medicine applications. As an example, iCell products are expected to contribute to the identification of novel drug candidates at the early stages of drug discovery as part of CDI’s recent $83 million partnership agreement with Roche.

In contrast to iCell products, MyCell products are customizable cells manufactured from cell bank- or researcher-provided samples, often from donors representing specific disease states.

“The MyCell line gives us the ability to put a disease in a dish,” noted Parker. “In addition to exhibiting phenotypes that enable drug discovery, toxicity testing, and disease modeling, MyCell differentiated cells allow researchers to investigate autologous therapies based on iPSC technology.”

The company has a grant from the California Institute of Regenerative Medicine to derive iPSCs from approximately 3,000 donor-derived samples representing 11 different diseases including liver diseases, cardiomyopathies, blinding eye diseases, Alzheimer’s disease, lung diseases, and neurodevelopmental disorders such as autism. “These cell lines,” Parker pointed out, “can be differentiated into one of six available MyCell cell types and then compared to corresponding normal, healthy cells.”

CDI’s drug discovery program was initiated about three years ago with the aim of leveraging human iPSC-derived cells to facilitate therapeutic discovery efforts. “We have an aggressive plan for supporting preclinical research programs involving cardiac and ocular diseases, as well as Parkinson’s disease, to enable IND filings,” detailed Dr. Nuwaysir. “We are actively seeking partners for these programs.”

Dr. Nuwaysir provided additional detail about CDI’s work to support Parkinson’s research: “We are making the specific neurons that patients lose in Parkinson’s disease. In small animal studies, results indicate the symptoms of Parkinson’s disease can be reversed.”

In June 2016, CDI expanded a research program begun in 2014 by entering into a Cooperative Research and Development Agreement (CRADA) with the National Eye Institute (NEI). NEI researcher Kapil Bharti, Ph.D. is working toward clinical trials investigating cell transplantation therapy for the treatment of retinal degenerative disease, including age-related macular degeneration, using retinal pigment epithelium derived from CDI’s iPSCs.

Last spring (April 2016), CDI in-licensed technology from Indiana University to use progenitor cells to create blood vessels. “We are pretty excited about the science,” stated Dr. Nuwaysir. “We want to build a therapeutic program around it, but we aren’t commenting on the status of that program.”

A dense culture of CDI’s iCell® Cardiomyocytes (with partially overlapping cells) fixed and immunostained for calponin (green), myomesin (red), and DNA (blue). The myomesin shows myofibrils inside the cells; the calponin, nonsarcomeric actin stress fibers.

Building an iPSC Community

 “Having access to cell biology is useful only if you can measure things, manipulate them, and understand how they perform in chemical space,” commented Parker. “Creating dialogue among customers and learning how people actually employ iPSCs is more valuable than simply providing information about tools.” This belief is exemplified by vendor-neutral events hosted by CDI—the annual iForum™ meetings in the United States and Europe.

The most recent iForum 2016 meetings were held last September in Philadelphia and last October in Paris. They were opportunities for researchers and world-class experts to share information about how they use differentiated iPSCs to address issues in predictive toxicology, drug discovery, regenerative medicine, and other areas. “The popularity of iForum,” Dr. Nuwaysir asserted, “shows that iPSCs are becoming increasingly valuable as research tools and emerging therapeutics, enhancing CDI’s reputation in the process.”

Cellular Dynamics International (CDI)

Location: 525 Science Drive, Madison, WI 53711
Phone: (608) 310-5100
Principal: Kazuyoshi Hirao, Chairman and CEO
Number of Employees: 160
Focus: CDI, a Fujifilm company, is the world’s largest developer of induced pluripotent stem cells (iPSCs). It produces billions of cells daily for drug discovery, toxicity testing, stem cell banking, and cell therapy development.
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