NBT Article Re: iPS Technologies (nov 2009)

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  • 1. n e ws f e atur e The gold rush for induced that iPS cells with only 1% background vector expression showed significantly different gene pluripotent stem cells expression patterns compared with iPS daughter cells in which the vectors had been excised. Epigenetic modifications, accumulated over a lifetime in donor somatic cells, are likely to As the first commercial ventures are formed around induced play a role in the efficiency of reprogramming pluripotent stem (iPS) cell research, who will have the freedom to and subsequent differentiation. Differentiation is challenging even with ES cells, says Ed Baetge, operate commercially remains a big unknown. Sarah Webb reports. CSO at Novocell in San Diego, because each line is genetically distinct, and culture conditions and other selective pressures can alter the state Research on induced pluripotent stem (iPS) cells the University of California, San Francisco, and of chromatin or DNA methylation as the cells continues at a breathtaking pace. Not only is James Thomson of the University of Wisconsin- differentiate. “The problem with iPS cells is that rapid progress being made in understanding the Madison delivered four reprogramming genes they’re more epigenetically variant depending basic mechanisms of reprogramming, but also with viral vectors. The presence of integrated on what source you make them from and how the first applications of this work are beginning vector sequences, however, is problematic, you reprogram them,” he says. “You already have to appear. In the past 18 months, iPS cells have particularly for clinical application. For one issues with [differentiating] ES cells, and you been used to generate disease-specific cells for thing, the potential for insertional oncogenesis magnify them with iPS cells.”© 2009 Nature America, Inc. All rights reserved. several disorders (mostly neurodegenerative)1–3, exists. In addition, “vectors always have a basal Another important issue, particularly for and a September issue of Nature describes the expression level, you can’t turn them off really,” clinical applications, will be a better under- use of iPS cells derived from patients with famil- says Rudolf Jaenisch standing of the ial dysautonomia to generate neurons to evalu- of the Whitehead molecular mecha- ate drug candidates4. That opportunity—to Institute for nisms of repro- create cellular models of disease and then use Biomedical Research gramming. Why them to screen for drug candidates—highlights at Massachusetts those four genes the promise of this technology. Institute of Technology reprogram cells and iPS cells offer a pathway to pluripotency in Cambridge. That another four genes unhindered by the ethical and practical obstacles has spurred a search don’t is not fully associated with research using human embryos for chemicals that understood, says Ian and human eggs. “Many of the pharmaceutical can moonlight for Ratcliffe, president companies were really concerned about using the reprogramming and CEO of Stemgent ES [embryonic stem] cells,” says Mahendra factors. in Cambridge, Rao, vice president of research in stem cells and Already, research- Massachusetts, and regenerative medicine at Invitrogen, part of Life ers have been able to San Diego. Even if Technologies, in Carlsbad, California. “Now that replace one or more you’re using proteins, they have an alternate to getting pluripotent cells of the reprogram- or eventually small it becomes an easier choice for them to begin ming genes with Induced pluripotent stem cells. Technology molecules, to repro- work with iPS [cells].” small molecules or for producing iPS cells is developing quickly. gram cells, he says, But many fundamental research questions proteins. And as they (Image courtesy of James Thomson, University “the FDA is likely to about the reprogramming process (by which look toward clinical of Wisconsin Stem Cell and Regenerative want to know what differentiated somatic cells are returned to an applications of iPS Medicine Center) is the mechanism of ES cell–like state) remain unanswered. And with cells, they’re focusing action of these mol- no patents issued as yet, but a raft of reprogram- on factors that can be added extracellularly to ecules if you want to put [these cells] into ming patents filed (75 and counting), intellec- reprogram cells. In May, an international group humans.” tual property (IP) and future freedom to operate of researchers reported reprogramming human remain uncertain. Undeterred, companies in this fibroblasts with the four recombinant proteins The murky waters of intellectual property space are crafting strategies to move forward, alone5. And in October, Sheng Ding of Scripps With advances in the field announced nearly by targeting unmet scientific needs, filing patent Research Institute in La Jolla, California reported weekly, numerous patent applications have applications and purchasing licenses to other IP, reprogramming human fibroblasts to iPS cells been filed, but no patents have been issued and building their knowledge base through in- using three small molecules6. Combinations of in either the US or Europe. As a result, com- house talent and strategic partnerships. At the small molecules with proteins are likely to be panies have freedom to operate within this same time, commercialization efforts are zero- most efficient for reprogramming, Ding pre- space until the patent offices make those ing in on near-term goals—reprogramming kits, dicts. decisions. “You have the tension that this cell lines for toxicology screening and disease However, the more challenging issue, just looks like a really attractive technology models (Table 1)—leaving therapies for later. according to Jaenisch, is the ability to dif- to commercialize. Then you have the chal- ferentiate iPS cells efficiently and predict- lenge that we’re not clear on what we can The new and the unknown ably into the cell types wanted. Background patent or what we can’t patent,” says Ken The initial technologies for producing iPS vector expression could be preventing iPS cells Taymor, executive director of the Berkeley cells reported by Shinya Yamanaka of Kyoto from differentiating as efficiently as ES cells. Center for Law, Business and the Economy University in Japan and the Gladstone Institute at Jaenisch’s group has done experiments showing in California. nature biotechnology volume 27 number 11 november 2009 977
  • 2. NE W S f e atur e Table 1 Selected companies focused on the commercialization of iPS cells Company Date founded Intellectual capital Venture capital Focus Cellular Dynamics 2004 Founders: James Thomson, $18 million Cardiotoxicity modeling and iPS cell– International Craig January, Timothy Kamp, Tactics II Stem Cell Ventures, Tactics derived products; industrializing produc- Igor Slukvin II Ventures and Wisconsin Alumni tion of iPS cells and cell-based tools Recent hire: Junying Yu Research Foundation Fate Therapeutics 2007 Founders: Philip Beachy, Sheng Ding, $22.5 million Adult and iPS cell–based therapies; find- Rudolf Jaenisch, Randall Moon, ARCH, Polaris and Venrock ing small molecules or biologics to guide David Scadden, Leonard Zon cell fate to produce therapeutics iPierian 2009 Scientific advisers include: George Daley, $31.5 million iPS cell–based drug discovery research Kevin Eggan, Corey Goodman, Kleiner Perkins Caufield & Byers, Konrad Hochedlinger, Douglas Melton, Highland Capital Partners, MPM Capital Lee Rubin, Deepak Srivastava and FinTech Global Capital Recent hire: John Dimos Stemgent 2008 Scientific advisers include: Sheng Ding, $14 million Tools and reagents for iPS and other Rudolf Jaenisch, Gordon Keller, HealthCare Ventures, Morgenthaler stem cell research Robert Langer, Douglas Melton, Ventures Lee Rubin, Bob Weinberg, Leonard Zon© 2009 Nature America, Inc. All rights reserved. The patent uncertainty centers around two technology moves forward and could be less using lentivirus vectors, which was co-developed critical questions, notes Rao. Will the patents dependent on earlier technology.” with Open Biosystems, in Huntsville, Alabama be based on the process or the source? In one The second question is how the patent (and a part of ThermoFisher, the instrument scenario, it’s possible that early discoveries office might distinguish iPS cells from other and reagent supplier). Stemgent provides a such as those by Yamanaka and Thomson pluripotent cells, Rao adds. This question variety of reagents, media and tools for cellular could receive broad patents and all companies becomes important when thinking about reprogramming, growth and differentiation. would need a license to use iPS cells. However, methods for differentiating pluripotent cell Companies with experience with human ES a broad patent seems unlikely, according to lines into specific cell types. The method for cells are looking at iPS cells alongside their work David Resnick, a patent attorney with Nixon differentiating an iPS cell might be identi- with ES cells. In December, Novocell announced Peabody in Boston, in part because of changes cal to that used with an ES cell. If so, patents a partnership with Shinya Yamanaka to explore in the patent office since the broad ES cell pat- already issued based on ES cell research might the development of iPS cells to produce pan- ents of the 1990s. “There’s concern in the pat- predominate. In addition, because of their creatic islet cells as a complement to the com- ent office that they don’t want to have such a age, some patents for that ES cell work may pany’s existing work in this area with ES cells. broad patent that it would stop people from soon revert to the public domain. Invitrogen is working to provide tools and being able to make and use iPS cells,” he says. Companies currently operating in this reagents for both cell types, Rao says. “If we have Because the original technology using viral space are protecting themselves by licens- the best tools for ES cells, those tools should be vectors has already been supplanted, “we know ing broadly. Reagents and tools company good for iPS as well.” that technology in itself is not commercializable,” Stemgent is talking with researchers with rel- says Taymor. The more significant question, evant technologies and licensing technology Collaboration as a catalyst Taymor adds, “is where the line gets drawn sub- in the research products area, says Ratcliffe. But for companies focused primarily on iPS sequent to Yamanaka, what’s patentable based He estimates that his company has purchased cells, moving forward from reagents and kits on his disclosure.” Taymor is currently analyzing more than 50 such licenses. In many cases toward cell lines and disease models in the com- 75 patent applications relating to reprogram- those licenses are for patent claims, rather mercial space has involved bringing together sci- ming technology to assess that question. Claims than issued patents. entific know-how, funding sources and partners related to methods are easier to show and are “I think that this [IP] space is complicated from academia or industry. “[Research is] just therefore more likely, notes Resnick. However, enough that there will be many roads to in its nascent period. In the current economic based on the recent history, “the latest and great- roam,” says Chris Kendrick-Parker, chief com- climate it’s hard to get money to do big research est method [for producing an iPS cell] seems mercialization officer of Cellular Dynamics projects in this space. People want products,” to have a half-life of several months,” he adds. International (CDI) in Madison, Wisconsin. Ratcliffe says. With decisions likely a few years off, he says, it “We believe that there’s going to be very little One such undertaking is a consortium wouldn’t be surprising if some technologies are space for blocking.” Although he believes his announced in May between Stemgent and obsolete before the patents are prosecuted. company has a strong IP position, he thinks Boston-based Fate Therapeutics, a private “The IP landscape around induced pluri- their execution as a business will be more drug discovery company founded by Jaenisch, potent cells is just as complicated as the IP important in the long run than their IP. among other luminaries in stem cell field. The landscape around the rest of the field of consortium, named Catalyst, brings together regenerative medicine,” according to Greg The money trail Stemgent’s growing catalog of reagents with Bonfiglio of Proteus Venture Partners in Current commercialization strategies are Fate Therapeutics’ research into stem cell– Palo Alto, California. However, he suspects focused around producing research tools for based therapeutics and provides access to both that the current uncertain and complex IP making iPS cells and using iPS cells in drug dis- products and knowledge base to a select group situation might not matter in the long run. “I covery. In April, ArunA Biomedical, a privately of clients. think that this technology is advancing very, held company in Athens, Georgia, specializing in “We believe there are a lot of precompetitive very rapidly, and with each advancement the stem cells, launched a kit for producing iPS cells technologies,” says Ratcliffe of Stemgent. “The 978 volume 27 number 11 november 2009 nature biotechnology
  • 3. n e ws f e atur e pharmaceutical and biotech companies want cell–derived cells, the company hasn’t ruled ceutical companies as they start to evolve toward the same sorts of tools and would like to see it out. these types of applications from a therapeutics them validated in a number of different ways.” perspective, as well as any other entity who has Such tools could include iPS cell–generated The proof is in the cardiomyocytes ideas about differentiation and cell therapy disease models or alternatively normal iPS CDI was formed to industrialize both the pro- potential.” cells differentiated into different lines for toxi- cess of reprogramming somatic cells to form cology screening. With an initial investment iPS cells and the differentiation of those cells iPS cells and pharma of a few million dollars, partners would pro- into useful cell types for toxicology screens and Large pharmaceutical companies are also vide the funding to support the research, says drug discovery. The company produces billions beginning to explore the iPS cell space. London- Paul Grayson, president and CEO of Fate of iPS cells each day using the plasmid-based based GlaxoSmithKline and the Harvard Stem Therapeutics. In return, they receive a license method developed by founder Jamie Thomson Cell Institute announced a 5-year, $25 million to the existing IP portfolio and the technology with recent hire Junying Yu7, and according collaboration in July 2008 that would pro- that results from Catalyst. No pharmaceutical to Kendrick-Parker, is producing cardiomyo- vide tools from stem cells including human companies have signed on yet. cytes for pharmaceutical companies, includ- ES cells and iPS cells for drug discovery. Four All of the Catalyst funds will go directly into ing Roche’s Palo Alto, California, research months later, New York–based Pfizer launched research, Grayson adds. Pharmaceutical part- facility. In the past few months, CDI has also its Regenerative Medicine group. Although ners will maintain rights to drug discoveries announced exclusive licensing agreements with the safety group at Pfizer is also looking at that they make using the common technology both Mount Sinai School of Medicine in New iPS–derived cell lines for toxicology studies, platform, but any improvements to the platform York and Indiana University–Purdue University the regenerative medicine group is specifi-© 2009 Nature America, Inc. All rights reserved. will be shared among Catalyst members, says Indianapolis for technology related to differen- cally focused on drug discovery using cell lines Scott Wolchko, Fate’s CFO. “So we are a devel- tiation of cardiomyocyte progenitor cells and derived from iPS and hES cells. One particular oper of the technology but also an end-user of methods for producing highly purified cardio- area of interest is in neurodegenerative diseases, the technology,” he says. Nonprofits and aca- myocytes. such as ALS and Huntingdon’s disease, says demic researchers would be able to license the “There really is an unmet need for models CSO Ruth McKernan. Catalyst technology for free. “I believe that we as to understand cardiotoxicity,” says Kendrick- The unit already has a publicized collabora- a company have a lot more to gain by pushing Parker. Several drugs have made it to the market tion with Novocell focused on using Pfizer’s our technology into the academic market than that have cardiotoxic profiles and that’s unac- library of small molecules toward the differen- by keeping those [inventions] internally,” says ceptable.” These cells have the added bonus tiation of human ES cells into pancreatic beta Grayson. of a physiological function that researchers cells. can monitor—a ‘heartbeat’—in addition to But as with other companies entering this Focusing on disease models other biochemical cues. In September CDI area, Pfizer sees itself as focusing on collabora- Another collaboration led to the creation of and VivoMedica, a Sittingbourne, UK, phar- tive opportunities. “When we entered this space, iPierian, formed in July through the merger maceutical technology company, launched we did so with the expectation that we would of S. San Francisco–based iZumi Bio, an iPS- CARDIOTOX, a consortium that will use CDI’s do a lot by collaboration because there are so cell drug discovery company, and Pierian. The cardiomyocytes in VivoMedica’s microelectrode many good academic and biotech groups out new company is focused on using iPS cells to arrays and data analysis techniques. The con- there,” McKernan says. “We want to partner so develop small molecules and biologics against sortium will include a group of pharmaceuti- that we can get right at the very front of science neurodegenerative diseases. Pierian’s founders, cal partners, who will validate the system as a as quickly as possible.” Harvard University professors George Daley, screening tool to predict the cardiac proar- The speed with which the science is progress- Douglas Melton and Lee Rubin, are all on the rhythmic potential in new drug candidates. ing characterizes all aspects of iPS cell research. scientific advisory board of the new company. This type of feedback from pharmaceutical Whereas most fields develop over years or even In addition, the company has hired young sci- companies is valuable, Kendrick-Parker says, decades, the explosion in iPS technology has entists such as John Dimos, a former postdoc in because rather than looking at standard cell developed “right before our eyes,” says Resnick. Kevin Eggan’s group at the Harvard Stem Cell biology markers, CDI gets information on how “It’s intriguing from a scientific and from a legal Institute and lead author on their Science paper the cardiomyocytes perform compared with point of view.” that demonstrated the differentiation of iPS existing model systems. “A lot of people can That pace of development seems unlikely to cell–based motor neurons from patients with make cardiomyocytes, but the key thing is, do slow any time soon. The promise of the field, for ALS2. The company is also collaborating with those cells respond to therapeutics or drugs in drug discovery or even personalized medicine, Shinya Yamanaka on other methods for generat- a way that’s expected?” he says. Consistency in without the barriers associated with research ing iPS cells. that response is what will give pharmaceutical with embryos or human eggs, has attracted tal- iPierian CEO John Walker emphasizes that companies confidence that a tool will fit their ented people, Bonfiglio says. “You can’t underes- the company will not be marketing research needs, he says. In December CDI will launch timate the power of that intellectual capital, and tools. Rather, the company will be focused on iCell cardiomyocytes, a commercially available it’s helped move the field along.” drug discovery applications. By developing kit that will include cryopreserved cells, media Sarah Webb, Brooklyn, New York cellular models from patients, they plan to use and other tools. those cells to both better understand the disease Although Kendrick-Parker is excited about the 1. Ebert, A.D. et al. Nature 457, 277–281 (2009). 2. Dimos, J.T. et al. Science 321, 1218–1221 (2008). and investigate novel pathways and novel targets opportunity that iPS cells provide to produce cell 3. Soldner, F. et al. Cell 136, 964–977 (2009). to intervene in the disease, says chief technology types with varying genetic profiles for drug devel- 4. Lee, G. et al. Nature 461, 402–406 (2009). officer Berta Strulovici. opment, CDI isn’t looking toward future commer- 5. Kim, D. et al. Cell Stem Cell 4, 472–476 (2009). 6. Lin, T. et al. Nature Methods, published online 18 Although iPierian is not currently looking cial cell therapies. Instead, he says, “we believe that October, 2009, doi10.1038/nmeth.1393. toward the therapeutic applications of iPS we look like a great partner, for either pharma- 7. Yu, J. et al. Science 324, 797–801 (2009). nature biotechnology volume 27 number 11 november 2009 979