Scaling Up Stem Cell Production for Clinical Trials

The opening of a multi-product cleanroom facility in early 2020 marks the beginning of a new chapter for FUJIFILM Cellular Dynamics Inc.

For more than a decade, this US subsidiary of Fujifilm has sold research-grade human induced pluripotent stem cell-derived cells to the pharmaceutical industry for screening drugs and modelling diseases in the laboratory. Now, with the ability to create cells designed to meet the strict US regulatory standards for current Good Manufacturing Practice (cGMP), the company is stepping into the realm of regenerative medicine and preparing for clinical testing of its stem cell–derived product candidates.

Getting to this point has been a trial in itself. “Ever since we decided to start cell therapy programmes, we had to go back and look at every reagent we buy, every method we use, the scalability of our protocols and more, and then re-develop and re-optimize everything for human therapeutic use,” says Chad Koonce, director of cardiac cell therapy at FUJIFILM Cellular Dynamics headquarters in Madison, Wisconsin.

To have the $21 million facility up and running, with manufacturing planned for 2020 and beyond, is “all really exciting,” Koonce says.

The company currently manufactures more than a dozen cell types — including nerve cells, immune cells, and organ-specific cells of the liver, brain and heart — all of research-grade quality. At the new ultra-clean production site, the company will begin to generate four types of cells ready for clinical development with potential for expansion into other areas.

The initial four are dopamine-producing neural cells, cardiac progenitor cells, retinal cells, and immune cells.

All are derived from human induced pluripotent stem cells (iPSCs) — skin or blood cells switched back to their pluripotent state. Using FUJIFILM Cellular Dynamic’s proprietary protocols, scientists coax the iPSCs to form highly pure populations of the specialized cells of interest.

CLOSE AT HEART

Koonce was among the team that developed the process for making GMP-grade heart muscle cells and their precursors, known as cardiac progenitor cells. The specified version of these cells, called cardiomyocytes, are easier to fabricate than the cardiac progenitor cells, notes Koonce, but studies have shown that these cells, when implanted in the heart, sometimes beat out of sync with neighbouring tissues, leading to potentially fatal arrhythmias. Cardiac progenitor cells are expected not to spontaneously contract at the time of injection, reducing this initial safety concern.

“The key is that these cells are primed to become cardiomyocytes,” Koonce explains. “We can inject these cardiac progenitor cells directly into the damaged area of the heart and these cells will then differentiate. We’re actually allowing the cells to further develop once engrafted.”

Koonce’s group is working with the team led by cardiologist, Emerson Perin, at the Texas Heart Institute in Houston to evaluate the cardiac progenitor cells in a pig model of chronic artery blockage. So far, Perin’s team has injected the cells into approximately 10 pigs with experimentally induced heart failure.

Running a catheter through each pig’s groin, they deliver hundreds of millions of cardiac progenitor cells directly at the site of injury. Using an electromechanical mapping system, they build three-dimensional renderings of the heart chamber before and after treatment. They also perform complete post-mortem tissue work-ups on pig hearts.

“The early sense we have is that this all looks very promising,” Perin says. “It’s true regenerative medicine.”