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The future is now
SAN FRANCISCO—Since the generation of the first induced pluripotent stem (iPS) cells just a few short years ago, researchers have been hard at work to push the envelope of discoveries in this area.
The results have supported theories that these breakthroughs could have a significant impact on how many diseases are treated, and many researchers say that today, iPS technology is poised to make its mark on drug discovery.
One venue where this sentiment was very much in play was a recent panel discussion titled "Cellular Reprogramming for Drug Discovery: Applying the Advancements in iPS Cell Technology Today," moderated by Dr. George Daley, director of Stem Cell Transplantation at the Children's Hospital and Dana Farber Cancer Institute, The Samuel E. Lux IV Chair in Hematology, and associate professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School. His lab was among the first to produce human iPS cells and disease-specific stem cells. As a clinician-scientist, Daley has extensive experience in translating promising science into novel therapeutics, and he co-founded iPierian Inc., a California-based biopharmaceutical company and leader in the application of iPS technology to drug discovery and development—and the company that hosted the panel discussion.
Induced pluripotent stem cells were first generated by Shinya Yamanaka's team at Kyoto University in Japan in 2006. Just four years since the first generation of iPS cells, their impact is only just beginning to be felt on drug research, Daley told ddn during a recent interview.
"Many groups are screening drugs against cellular defects in patient-derived iPS cells," he says. "Some groups have reported success … I anticipate wider use and more success in the future, as more and more groups apply this new strategy."
Daley notes that there are plenty of advantages to the use of iPS cells by researchers.
"Lots of drugs have been screened in cell-based assays (e.g, cancer chemotherapy), but almost never against disease-specific cells," he says. "The ability to screen against cells that are actually affected by disease, rather than some imperfect surrogate, makes it more likely the drug will be successful in patients."
Additionally, iPS cells continue to have the potential to rework the current drug discovery system.
"If the field can show that testing drugs against specific human diseased cells in vitro generates a higher probability of success, more and more companies will adopt the strategy," Daley says.
Daley also points out that the adoption of the technology could impact drug development in the coming years. He notes that the hope is that success rates of new drugs will improve, because the disease-specific cells allow a "clinical trial in a dish."
Exactly which therapeutic areas could benefit the most from iPS cell technology remains difficult to gauge, according to Daley.
"I founded iPierian on the presumption that neurodegenerative disease was the most likely to benefit from iPS technology first," he explains. "The methods for making specific types of nerve cells affected by diseases like ALS and Parkinson's are well established. The promise that the iPS-derived nerve cells affected by these diseases will behave in the Petri dish like they do in the patient convinced me to start iPierian. My own area of interest is blood disease, and although we've made lots of progress in treating blood conditions like anemia and leukemia, many patients still die prematurely and we're planning to screen for drugs against blood cell populations from disease-specific iPS cells."
The panel discussion focused on the applications of iPS cell technology to drug discovery and it included Dr. Corey Goodman, chairman of the board of directors of iPierian; Dr. Robert Pacifici, chief science officer of the Cure Huntington's Disease Initiative Foundation (CHDI); Dr. Alan Trounson, president of the California Institute for Regenerative Medicine; and Sir Ian Wilmut, director of the Scottish Centre for Regenerative Medicine at the University of Edinburgh.
During the session, scientific experts discussed recent progress that demonstrates the immediate utility of iPS cell technology for discovering new therapeutics as well as its potential to reduce both the time and cost of drug discovery. Participants in the iPierian session, which was held in San Fransisco this summer, see iPS cell technology as a watershed moment in drug discovery.
Wilmut says that since he first heard of the development of iPS technology, he believed it would be a transforming technology.
"I still believe that," he says. "Our view, which we believe is a very general one, is that the cells at the present time are extremely beneficial for research to study normal developments and the disturbances that develop in disease. We look forward to the time when after the procedures have been refined that they can be used in therapy."
Pacifici points out that the CDHI is focused on Huntington's disease, a monogenetic disorder with late onset.
"The ability now to harvest the repertoire of different genetic backgrounds, and things that have different modifier genes that would affect the age of onset are things that we are excited about," he said.
As a not-for-profit, the CDHI is involved with researchers from academia as well as the public sector, and it also reaches out to companies that have cutting-edge technologies "that we feel would precipitate an inflection point in our ability to do drug discovery," Pacifici says. "We feel that this technology is definitely going to fit into that category, especially in terms of cost, cycle time, throughput and quality."
Goodman points out that iPS cell technology could prove to be a boon for Big Pharma. Offering his perspective of what Big Pharma's needs are and how iPS cell technology can benefit them, he noted that there are enormous unmet medical needs and Big Pharma "is on the ropes."
"It is often said that one out 10 drugs make it to clinic," he says. "If it were only that good, I wouldn't be saying it was a problem. The truth is, it is really one out of 35. Which is why instead of a chemical entity costing $1 billion, it costs $4 billion, on average."
Moreover, Goodman points out that most of the Big Pharma pipelines are in worse shape than they care to admit.
"If you are going against single targets and most of your data comes from mice and rats, the truth is that you have enormous attrition in humans," he says. "You need more human biology."
As a developmental biologist, Goodman says he is excited about iPS cells and the notion of testing directly on human cells.
"You can actually test in a dish on actual human cells," he says.
Trounson notes that "if you can create the disease in a dish, and you can get the genotype to occur, then you have a model that you can study genetically."
According to Trounson, if researchers get more candidate molecules, it will benefit human disease.
"I'm incredibally optimistic," he says. "I know there will always be disappointments along the trial, but this is a huge revolution that adds to our capacity that we have never had before. "
Daley points out that regulators will likely still require the same amount of animal work in testing, but the use of iPS cells will improve efficacy.
"Clinically, the bar is going to stay the same. The FDA is going to look for efficacy and the lack of side effects or tox to balance efficacy in patients. I think what is going to be so important is that we will be more successful," he says. "Instead of the attrition being one out of 35 or one out of 40 drugs, that we get back to one out of 10 or even better numbers. We are going to jump quicker to getting human data. You are going to know sooner what drugs have a chance at helping human patients."
Wilmut says the use of iPS cells and stem cells can be viewed as complimentary technologies.
"I don't think the iPS technology is something that is going to solve all of the problems all on its own," he adds. "It will be extremely useful to be able to make genetic-targeted changes."
Ultimately, Goodman says it will be up to Big Pharma to enter the race and pick up the mantle of iPS cell technology or be left at the starting gate.
"I think the next 10 years are going to be dynamic," he says. "Some pharmas are going to embrace the new technology faster than others."
Goodman predicts that throughout Big Pharma, there will be pioneers in the new technology and there will be followers.
"The day one (Big Pharma) gets positive phase II positive proof of concept on a drug without side effects that came from this technology, that's going to push them all over," he concludes. "I think the world of drug discovery will look different 10 years from now. There will be some of the familiar pharma names, but they are going to have to adapt to survive."
Overall, Daley points out that there is a bright future for iPS cell technology.
"The field continues to move rapidly ahead with refinements in the reprogramming process itself—faster, more efficient, more complete," he says. "Moreover, there's lots of effort to make specific tissues in the Petri dish, not only for drug screening but also for potential transplantation with a patient's own cells. This is the long term aspiration of stem cell biology—to deliver cells as medicines."