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Scripps Method May Enable Commercial-Scale Manufacture of iPSCs

NEW YORK (GenomeWeb News) – Scientists at the Scripps Research Institute have developed a method to chemically induce pluripotent stem cells from human fibroblasts more efficiently and quickly than previous methods, according to a research paper published this week.

The advance could pave the way for manufacturing of "pharmaceutical grade" pluripotent stem cells on a commercial scale for drug discovery, research, and therapeutic use, according to stem cell company Fate Therapeutics, which sponsored the research and which has an exclusive license to underlying intellectual property.

In addition, the new method could be a boon to Fate and stem cell research tool company Stemgent, which have partnered under a program called Catalyst to provide iPSCs as research and drug-discovery tools to pharmaceutical and biotech companies.

In a research paper published yesterday in the advance online edition of Nature Methods, a team led by Sheng Ding, an associate professor of chemistry at Scripps, described the technique, which involved treating human fibroblasts with a "cocktail" of three small-molecule compounds.

The method was able to generate iPSC colonies that could be stably expanded over more than 20 passages, closely resembled human embryonic stem cells in terms of morphology and pluripotency marker expression, and could be differentiated into derivatives of all three germ layers both in vitro and in vivo.

In addition, the small-molecule treatment represented a more than 200-fold improvement in reprogramming efficiency in about half the time as previously reported methods, including a four-compound treatment reported by Ding and colleagues earlier this year.

"Before iPSCs can be used in therapies or for drug discovery, we needed to find a way to 'industrialize' the technology to quickly and efficiently create iPS cells," Scott Wolchko, CFO of Fate Therapeutics, wrote in an e-mail to GWDN.

"The low efficiency and slow speed of reprogramming, which had a success rate of roughly one in 10,000 cells and took about four weeks from start to finish, presented a potentially greater problem for the ultimate applications of human iPSCs," Wolchko added. "This study shows that with three new chemicals we can create 200 times more cells in half the time as the regular methods."

In a statement, Fate President and CEO Paul Grayson, said that the discovery represented the clearing of "yet another major hurdle required for the widespread commercial use of iPSCs for drug discovery and patient therapies."

Indeed, ever since iPSCs were first produced from mouse cells in 2006 and human cells in 2007, researchers have been eager to perfect the induction process to be able to produce a steady supply of reprogrammable cells for research and therapeutic use and skirt the ethical quandary surrounding the use of human ESCs.

The first reported methods for inducing pluripotency involved using plasmids or virus vectors to introduce genetic elements into the cells. But these methods were relatively inefficient, not to mention potentially unsafe for therapeutic use due to possible oncogenic transformation of cells.

In November of last year, Ding's team demonstrated that small molecules can replace viral transduction of certain factors critical for iPSC reprogramming; and followed that study up in April with research demonstrating the use of only engineered proteins and small molecules could create pluripotent stem cells.

While that method of reprogramming was "truly ground-breaking," Wolchko said, it did not "substantially address the need to improve speed or efficiency."

In this week's paper, Ding and colleagues demonstrated that three new small molecules "can provide drastic improvement to speed and efficiency, and we expect that these new chemicals will easily translate to any reprogramming method, including protein, small molecule, and other more traditional methods of genetic-based reprogramming," Wolchko said.

The upshot is that scientists may be able to much more quickly and efficiently produce iPSCs that can then be differentiated into cells such as hepatocytes and cardiomyocytes for drug discovery and basic research – a market niche in which Fate feels it holds a strong position.

Fate holds an exclusive license to previous related IP generated in Ding's laboratory and in labs at the Whitehead Institute of Biomedical Research; as well as IP from a number of iPSC labs at prominent institutions such as Stanford University; the University of Washington; Harvard University; Massachusetts General Hospital; and Children's Hospital Boston.

And, while it is first and foremost developing chemically induced PSCs for eventual therapeutic use, Fate also has an alliance with Stemgent dubbed "Catalyst" to provide customers with iPSCs for drug discovery and development.

"We believe there is a great need for pharmaceutical grade iPSCs, reprogrammed cells that can be produced and differentiated without genetic modification at commercial scale quantity, quality, and consistency," Wolchko said, adding that it is in "active and ongoing" discussions with potential pharma partners.

"Our potential pharma and biotech partners recognize that major hurdles for commercial adoption of iPSC technology have been cleared with the advent of protein-based reprogramming and conditions that substantially improve efficiency and speed," Wolchko said.

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