LA JOLLA, Calif.– Fate Therapeutics Inc. has unveiled thenext generation of human induced-pluripotent stem cells (iPSCs) using acombination of small molecules that significantly improves the speed andefficiency of reprogramming.
The discoveries, which were made by Dr. Sheng Ding,associate professor of The Scripps Research Institute (TSRI) and scientificfounder of Fate Therapeutics, under a research collaboration between FateTherapeutics TSRI and represent a more than 200-fold improvement inreprogramming efficiency and reduce the reprogramming period to two weeks ascompared 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-moleculedrug discovery."
Earlier this year, under a research collaboration with FateTherapeutics and TSRI, Ding and his team of scientists became the first groupto generate iPSCs using non-viral, non-DNA based reprogramming methods. Insteadof inserting the reprogramming factors of Oct 3/4, Sox2, Klf4 and c-Myc withDNA-based methods, such as viruses or plasmids, the scientists engineered andused recombinant proteins to reprogram cells without genetic modifications.
The scientists found that those reprogrammed embryonic-likecells—dubbed "protein-induced pluripotent stem cells," or "piPSCs"—fromfibroblasts behave indistinguishably from classic embryonic stem cells in theirmolecular and functional features, including differentiation into various celltypes, such as beating cardiac muscle cells, neurons, and pancreatic cells.
Before iPSCs can be reliably used as therapeutics orproduced on a commercial-scale for drug discovery purposes, there are twothings that are necessary: a safe means of reprogramming cells and a rapid andefficient source of cells. Wolchko says until now, nobody has addressed thefundamental problem of efficiency—iPSC generation was still a very slow andinefficient process.
The findings of Ding and his colleagues were publishedrecently in the advanced online edition of the scientific journal NatureMethods.
As compared to using the four reprogramming factors of Oct3/4, Sox2, Klf4 and c-Myc alone, Ding discovered a combined chemical approachthat dramatically improves (> 200 fold) the generation of iPSCs from humanfibroblasts within two weeks of retroviral transduction. The iPSC coloniesgenerated by the Ding team using a 3-compound cocktail could be stably expandedover the long term (20+ passages), closely resembled human embryonic stem cellsin terms of morphology and pluripotency marker expression and could bedifferentiated into derivatives of all the three germ layers, both in vitro and in vivo.
"Once we achieved reprogramming with cell-penetratingproteins, we targeted certain biological pathways that might improve speed andefficiency so as to enable the commercial scale production of patient-specificiPSCs for medical use," says Ding. "When combined with non-viral, non-DNA based methods for iPSCgeneration, 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 histeam have done two things: They have cut in half the time it takes to reprogramadult cells back into embryonic-like, induced pluripotent stem cells (iPSCs),and they were 200 times more efficient in their cell production (the number ofstem 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 thecreation of "pharmaceutical grade" iPSCs, reprogrammed cells that can beproduced without genetic modification at commercial-scale quantity, quality andconsistency, and continues to bolster the leadership position of FateTherapeutics in industrialized iPSC technology, Wolchko says.
The company is developing minimally invasive techniques forreprogramming and differentiation and has exclusively in-licensed from TSRI andthe Whitehead Institute for Biomedical Research a intellectual propertyportfolio 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 theundifferentiated iPS cells can be generated with unlimited amount and do nothave to be maintained in the protein cocktail.
"Once reprogrammed, iPSCs are maintained in conventionalchemically defined media," Ding notes.
Paul Grayson, president & CEO of Fate Therapeutics,points out that while recent studies have reported improved methods ofreprogramming, those techniques have relied on further genetic manipulation orhave not otherwise addressed a fundamental reprogramming challenge—that iPSCgeneration is still a very slow and inefficient process and results in aheterogeneous population of cells.
"Once again, Dr. Ding and his team are the first group toclear yet another major hurdle required for the widespread commercial use ofiPSCs for drug discovery and patient therapies," he says.
Wolchko also points out that there is a protocol by whichthe proteins are added for the cell to be reprogrammed. He adds that there areno safety issues.
"Just like drug discovery requires translation forcommercial application, reprogramming and applying reprogramming requires adegree of translation," he says. "This is a non-genetic based non-genetic modifiedmeans of being able to reprogram cells. It is not biotech and it is notDNA-based."
Fate Therapeutics has clear plans for the technology andwill develop its own therapeutics and use the technology in partnerships,Wolchko says.
"Given the vast number of applications associated with cellreprogramming, the answer is that we are doing both," he says. "We areaggressively looking for partners to commercialize the technology as we areinterested in using that technology in our own therapeutic discovery efforts.We are interested in making sure this technology is very available. There are anumber of ways to take this to the marketplace."
Moving forward, Wolchko notes that measuring the truesuccess of iPSC technology is years away.
"It has significant potential with regard to personalizedcell therapy, in the long-term perspective," he says. "In the short term, beingable to use iPSC technology to recapitulate rare cell populations and studythose populations from a biological perspective to assist in drug discovery isour interest."
Fate Therapeutics closes $30 million Series B financing
LA JOLLA, Calif.—Fate Therapeutics has completed a $30million Series B financing which will allow it to expand its stem celldiscovery engine.
Fate Therapeutics is developing its lead stem cellmodulator, FT1050, to enhance hematopoietic stem cell (HSC) proliferation andhoming. The small molecule is currently undergoing clinical testing at the DanaFarber Cancer Institute and Massachusetts General Hospital in adult patientswith hematologic malignancies, such as leukemia and lymphoma, who haveundergone nonmyeloablative conditioning therapy and are in need of HSC support.The Phase Ib study is intended to determine the safety and tolerability ofintroducing FT1050 during the standard course of dual umbilical cord bloodtransplant and will also track HSC engraftment efficiencies and patientoutcomes.
"With this Series B financing, we have raised the necessaryfunds to build on the pioneering research and foundational intellectualproperty of our scientific founders for human cell reprogramming and to enablethe commercialization of our pharmaceutical grade iPSC technology," said ScottWolchko, chief financial officer of Fate Therapeutics. "The company iswell-positioned to aggressively advance its leading iPSC technology platformfor use in its own internal discovery programs as well as with strategicpartners."
The three co-leaders of the company's Series A financing, ARCH VenturePartners, Polaris Venture Partners and Venrock, also participated in the latestround of financing. In conjunction with the funding, Weissman also joined thecompany's board of directors.