15 May Stem cell therapies are fast approaching
Madison, Wis. – In an earlier column about the recent Stem Cell Symposium held on the Promega Campus, I extolled the exciting frontier of stem cell basic science that was on display; however, it was just as interesting to catch up with local stem cell researchers who attended the Symposium because I caught a glimpse of the current status of stem cell science in the Madison area.
Health benefits of embryonic stem cells
For instance, I ran into Tim Kamp, an associate professor in the University of Wisconsin-Madison School of Medicine’s Department of Physiology. Kamp, who along with Professor Jamie Thomson, recently developed a reliable way to derive human heart cells from embryonic stem cells (ESCs).
About four years ago, I first met Kamp in his UW-Madison office to learn about his research. At that time, researchers knew that when given the chance, human ESCs haphazardly differentiate in tissue culture into all the different tissue types. Kamp, using a microscope, had been able to find among the clutter of different cells a few well-developed heart cells that actually were beating!
Using a steady-handed robot, Kamp inserted a very fine probe into a beating heart cell and measured its depolarization or the exchange of ions across its membrane, which constitutes the electric current that causes heart muscle to beat. With this, he recorded an “EKG” on a single human heart cell that changed as expected when he added it to the culture, a drug often given to heart patients.
Currently, animal models are the best way to measure pharmacological effects of drugs on the heart, an important but insufficient model since 30 percent of drug failures are due to cardiotoxicity. Clearly, we need ways to test drugs on human heart cells, but until the advent of ESCs, there was no reliable way to obtain and grow them in the lab. Now, being able to derive functional heart muscle cells from ESCs provides an important option for testing drugs on real human heart tissue, thereby improving the safety and efficacy of new drugs. At least this was Kamp’s goal four years ago when I talked with him in his office.
Things seem to be progressing well. A couple of years ago, Kamp and his co-workers launched the local biotechnology company, Cellular Dynamics International, in order to bring this technology to fruition. In early March, Roche Palo Alto reached an agreement with CDI to begin using their ESC-derived heart cells for testing the cardiotoxicity of candidate drug compounds.
Using ESCs to derive fully functional mature cell types for testing potential drugs and toxins directly on human tissues is an under-appreciated and poorly communicated application for ESCs, but one that will soon be widely employed in the pharmaceutical industry. Thus, human ESCs will likely play an important role in human health, even if they are never used to directly treat human disease.
Kamp indicated that similar screening methods are being developed for other tissue cell types derived from human ESCs.
Treating neurological diseases
A few years ago, I attended a seminar by UW-Madison neuroscientist, Clive Svendsen, who showed a video clip of patients with Parkinson’s disease before and after treatment with a nerve cell factor known as GDNF. The result was a dramatic slowing of disease progression in treated patients.
As encouraging as this therapy was, it remains highly experimental since GDNF cannot cross the blood-brain barrier and must be delivered by cannula – a thin tube inserted deep into the brain area affected by Parkinson’s disease – not an attractive long-term option.
Furthermore, GDNF therapy only retards the progressive loss of dopamine producing neurons that is characteristic of Parkinson’s disease; it does not reverse the process. Therefore, this will not likely benefit patients with advanced disease who have lost too many of these critical cells. This is where the hope of stem cell therapy merges with the other great therapeutic hope – gene therapy.
For instance, ESCs alone are not likely to be much of a benefit for patients with Parkinson’s because stem cell-derived, dopamine-producing neurons transplanted in the brains of Parkinsonian patients likely will suffer the same fatal fortune as their endogenous predecessors. However, combine stem cell regeneration of the neurons with in situ production of GDNF via gene therapy technology and you just may be able to sustain dopamine-producing cells for the long term. Or so goes the hope.
A similar idea is being tested in Svendsen’s lab for treating amyotrophic lateral sclerosis; also know as ALS or Lou Gehrig’s disease. Like Parkinson’s, ALS is caused by the progressive and irreversible loss of certain critical neural cells in the brain. Svendsen’s lab has developed rat and primate models of ALS and using human fetal-derived neural stem cells, in conjunction with gene transfer technology, have successfully implanted fully functional, GDNF producing neurons in brains of these ALS animals. The results are very encouraging at this point – they see long-term survival of the transplanted cells and sustained production of GDNF, and these correlate with resolution of symptoms.
This is not the first example using ESCs to successfully treat human diseases in animal models, but ESCs have not yet made it into the clinic. Human trials will likely begin in the next year or two and the FDA is now considering how to best monitor them for safety and efficacy – not a trivial undertaking, but stay tuned.
Moving stem cell science along
At the symposium I also had the chance to connect with Eric Forsberg, the recently appointed director of the WiCell Research Institute. This is the non-profit spin-off from the Wisconsin Alumni Research Foundation that provides support for stem cell researchers at UW-Madison.
According to Forsberg, WiCell not only maintains the National Stem Cell Bank, it also engages in outreach activities and provides core services for stem cell researchers that are not found elsewhere on the UW-Madison campus. Forsberg pointed out that WiCell also is happy to provide such support and training for private stem cell companies in order to foster the development of cell-based medicine in Wisconsin.
Forsberg hopes to soon partner with the Waisman Center on the UW-Madison campus to begin a trial run to grow clinical-scale batches of ESCs under the conditions that are required in order to use the cells to treat patients. The Waisman Center has the facilities to produce biological materials for clinical use.
This will be a proof-of-principle endeavor designed to show that ESCs can be produced in clinically relevant quantities while maintaining their state of differentiation. Unforeseen problems, the bane of any biotechnology research, will be identified and resolved during this trial run so they will be ready when the time comes to quickly move ESCs into clinical trials.
First trial applications
We rapidly approach the day when ESCs will be used in experimental therapies of human diseases. In all likelihood, the first trials will use blood or bone marrow products derived from ESCs as a donor source for marrow transplantation or red cell transfusion.
Recent columns by Steve Clark
• Steve Clark: Stem cell frontier on display at Promega
• Steve Clark: Madison biotech company happy to ride the coattails of competitor
• Steve Clark: Understanding the science is key to predicting biotech success
• Steve Clark: Predicting success of early-stage biotechnology
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