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LA JOLLA, Calif.– Fate Therapeutics Inc. has unveiled the next generation of human induced-pluripotent stem cells (iPSCs) using a combination of small molecules that significantly improves the speed and efficiency of reprogramming.
The discoveries, which were made by Dr. Sheng Ding, associate professor of The Scripps Research Institute (TSRI) and scientific founder of Fate Therapeutics, under a research collaboration between Fate Therapeutics TSRI and represent a more than 200-fold improvement in reprogramming efficiency and reduce the reprogramming period to two weeks as compared to methods using only the four reprogramming factors (Oct 3/4, Sox2, Klf4 and c-Myc).
"I think Scripps has been doing cutting-edge research, especially in the stem cell area, for a number of years," notes Scott Wolchko, CFO of Fate Therapeutics. "They have experience specifically in small-molecule drug discovery."
Earlier this year, under a research collaboration with Fate Therapeutics and TSRI, Ding and his team of scientists became the first group to generate iPSCs using non-viral, non-DNA based reprogramming methods. Instead of inserting the reprogramming factors of Oct 3/4, Sox2, Klf4 and c-Myc with DNA-based methods, such as viruses or plasmids, the scientists engineered and used recombinant proteins to reprogram cells without genetic modifications.
The scientists found that those reprogrammed embryonic-like cells—dubbed "protein-induced pluripotent stem cells," or "piPSCs"—from fibroblasts behave indistinguishably from classic embryonic stem cells in their molecular and functional features, including differentiation into various cell types, such as beating cardiac muscle cells, neurons, and pancreatic cells.
Before iPSCs can be reliably used as therapeutics or produced on a commercial-scale for drug discovery purposes, there are two things that are necessary: a safe means of reprogramming cells and a rapid and efficient source of cells. Wolchko says until now, nobody has addressed the fundamental problem of efficiency—iPSC generation was still a very slow and inefficient process.
The findings of Ding and his colleagues were published recently in the advanced online edition of the scientific journal Nature Methods.
As compared to using the four reprogramming factors of Oct 3/4, Sox2, Klf4 and c-Myc alone, Ding discovered a combined chemical approach that dramatically improves (> 200 fold) the generation of iPSCs from human fibroblasts within two weeks of retroviral transduction. The iPSC colonies generated by the Ding team using a 3-compound cocktail could be stably expanded over the long term (20+ passages), closely resembled human embryonic stem cells in terms of morphology and pluripotency marker expression and could be differentiated into derivatives of all the three germ layers, both in vitro and in vivo.
"Once we achieved reprogramming with cell-penetrating proteins, we targeted certain biological pathways that might improve speed and efficiency so as to enable the commercial scale production of patient-specific iPSCs for medical use," says Ding. "When combined with non-viral, non-DNA based methods for iPSC generation, we believe these discoveries create a powerful platform for safer, more efficient reprogramming of human somatic cells."
With this research, Wolchko points out that Ding and his team have done two things: They have cut in half the time it takes to reprogram adult cells back into embryonic-like, induced pluripotent stem cells (iPSCs), and they were 200 times more efficient in their cell production (the number of stem cells produced per batch) in the process.
"This is the most rapid and efficient method we've seen," Wolchko says.
This latest advancement also has broad implications for the creation of "pharmaceutical grade" iPSCs, reprogrammed cells that can be produced without genetic modification at commercial-scale quantity, quality and consistency, and continues to bolster the leadership position of Fate Therapeutics in industrialized iPSC technology, Wolchko says.
The company is developing minimally invasive techniques for reprogramming and differentiation and has exclusively in-licensed from TSRI and the Whitehead Institute for Biomedical Research a intellectual property portfolio related to iPSC technology dating back to November 2003.
According to Ding, the applications of this breakthrough "efficiently and easily produce better iPSCs for various iPSC applications, which have been well discussed in literatures." Ding also notes that the undifferentiated iPS cells can be generated with unlimited amount and do not have to be maintained in the protein cocktail.
"Once reprogrammed, iPSCs are maintained in conventional chemically defined media," Ding notes.
Paul Grayson, president & CEO of Fate Therapeutics, points out that while recent studies have reported improved methods of reprogramming, those techniques have relied on further genetic manipulation or have not otherwise addressed a fundamental reprogramming challenge—that iPSC generation is still a very slow and inefficient process and results in a heterogeneous population of cells.
"Once again, Dr. Ding and his team are the first group to clear yet another major hurdle required for the widespread commercial use of iPSCs for drug discovery and patient therapies," he says.
Wolchko also points out that there is a protocol by which the proteins are added for the cell to be reprogrammed. He adds that there are no safety issues.
"Just like drug discovery requires translation for commercial application, reprogramming and applying reprogramming requires a degree of translation," he says. "This is a non-genetic based non-genetic modified means of being able to reprogram cells. It is not biotech and it is not DNA-based."
Fate Therapeutics has clear plans for the technology and will develop its own therapeutics and use the technology in partnerships, Wolchko says.
"Given the vast number of applications associated with cell reprogramming, the answer is that we are doing both," he says. "We are aggressively looking for partners to commercialize the technology as we are interested in using that technology in our own therapeutic discovery efforts. We are interested in making sure this technology is very available. There are a number of ways to take this to the marketplace."
Moving forward, Wolchko notes that measuring the true success of iPSC technology is years away.
"It has significant potential with regard to personalized cell therapy, in the long-term perspective," he says. "In the short term, being able to use iPSC technology to recapitulate rare cell populations and study those populations from a biological perspective to assist in drug discovery is our interest."
Fate Therapeutics closes $30 million Series B financing
LA JOLLA, Calif.—Fate Therapeutics has completed a $30 million Series B financing which will allow it to expand its stem cell discovery engine.
Fate Therapeutics is developing its lead stem cell modulator, FT1050, to enhance hematopoietic stem cell (HSC) proliferation and homing. The small molecule is currently undergoing clinical testing at the Dana Farber Cancer Institute and Massachusetts General Hospital in adult patients with hematologic malignancies, such as leukemia and lymphoma, who have undergone nonmyeloablative conditioning therapy and are in need of HSC support. The Phase Ib study is intended to determine the safety and tolerability of introducing FT1050 during the standard course of dual umbilical cord blood transplant and will also track HSC engraftment efficiencies and patient outcomes.
"With this Series B financing, we have raised the necessary funds to build on the pioneering research and foundational intellectual property of our scientific founders for human cell reprogramming and to enable the commercialization of our pharmaceutical grade iPSC technology," said Scott Wolchko, chief financial officer of Fate Therapeutics. "The company is well-positioned to aggressively advance its leading iPSC technology platform for use in its own internal discovery programs as well as with strategic partners."
The three co-leaders of the company's Series A financing, ARCH Venture Partners, Polaris Venture Partners and Venrock, also participated in the latest round of financing. In conjunction with the funding, Weissman also joined the company's board of directors.