CHICAGO - The discovery of induced pluripotent stem (iPS) cells was made a scant three years ago, but already there is evidence of their unprecedented value in drug discovery and development.
IPS cells can be differentiated to scarce cell types such as cardiomyocytes and hepatocytes for use in preclinical toxicology. They also can be used to produce cell types that are practically impossible to obtain from other sources, such as different classes of neurons, cells from individual patients and cells that are models of specific diseases, for use in phenotypic screening.
"There have been presentations on iPS cells for the past two years at BIO, but these were about the science. We can now move beyond the science to discuss the commercial aspects of iPS cells," Joseph Ruiz, vice president of Research at Transposagen Inc., of Lexington, Ky., delegates Tuesday at the Biotechnology Industrial Organization international conference.
Dushyant Pathak, vice president of business development at iPerian Inc. of San Francisco, said iPS cells offer "game changing" potential in drug discovery. "The field has moved incredibly rapidly. In two years at iPerian we have shown we can generate hits and leads from iPS screens."
The field of iPS cells has seen a fantastic flowering since the technique of reprogramming somatic adult skin cells was first reported in 2006 by Shinya Yamanaka. That removed the ethical constraints imposed by the use of human embryonic stem cells, allowing work to apply pluripotent cells to move forward swiftly, both in terms of the most suitable reprogramming tools, and the best methods to control the forward differentiation of iPS cells into the desired cell type, noted Malcolm Fraser of Notre Dame University.
"We've been able to show they are functionally equivalent to human embryonic stem cells, but why would we prefer them?" Fraser said.
He suggested the main reasons are that they are potentially easier to standardize for use in cellular assays, they can be derived from individual patients, opening the way to highly relevant disease models, and there are no ethical concerns.
"This is a major advance because many companies prefer not to work on embryonic stem cells, even for assaying purposes," Fraser said.
Although there are different routes to generating iPS cells, ranging from delivery of DNA via an integrating adenoviral vector, to excisable vectors, and on protein and small-molecules reprogramming agents, there are drawbacks to each.
The technology for excising DNA after transformation is not available for human cells as yet, and all other vectors leave some exogenous DNA in the iPS cells. While using proteins or small molecules to drive reprogramming does not have that drawback, there are issues of maintaining pluripotency and of off-target effects. Those problems mean the prospect of using iPS cells in cell therapy remains a distant prospect, Fraser said.
However, Ruiz suggested it is not too early to be thinking about how to manufacture iPS cells for clinical trials. While the FDA has no firm rules as yet on cell therapies, there are a number of key issues, such as control of cell production processes, defining release specifications, defining the eligibility of human donors, and so on. "We need to be looking now and assessing what are the potential roadblocks," Ruiz said.
There may be many obstacles en route to their use in cell therapy, but iPS cells are already proving to be an important new tool for drug discovery and development, according to Chris Kendrick-Parker, chief operating officer of Cellular Dynamics International Inc., of Madison, Wis. At present cellular assays are limited to transformed cells, which though available in unlimited quantities are genetically unstable, and primary cells from cadavers, which are in short supply.
"IPS cells are the answer to these problems. They are stable in growth and available in unlimited quantities," Kendrick-Parker noted.
In addition, they can become any cell in the body, and can be generated from a variety of different tissues, including skin and blood. Cellular Dynamics is currently generating 1 billion iPS cells per day. It takes 30 days to differentiate these into cardiomyocytes cells, which beat in culture for two weeks. "They can be used for acute and chronic exposure to drugs," Kendrick-Parker said.
Having developed a robust platform technology for the production of cardiomyocytes, the company is now starting to apply that to generate other cell types. "We truly believe iPS cells can be used for cell models. The number of lines will increase, to include disease models, gender-specific lines and so on, and new reprogramming methods will be developed," Kendrick-Parker added.
Pathak said iPerian also is taking an industrial approach to the development of its iPS-derived cell lines, to ensure the screens it develops will work in the hands of CROs and pharma partners. "This will allow us to use them at all steps along the drug discovery platform from target discovery and validation, to profiling existing drugs in the appropriate cell type, triaging programs, and doing indication extension."
Eventually that will lead to the definitive in vitro clinical trial, in which panels of cells are collected reflecting the population it is hoped to treat. "For the first time you can start [drug discovery] with the patient population," Pathak said.