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Jun 15, 2013 (Vol. 33, No. 12)

ReGen Med: Straight Out of Mythology

  • Technical Issues

    “Developing approaches to repair tissue damage is one of the areas of greatest unmet need in multiple sclerosis,” says Jeffrey A. Cohen, M.D., professor at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. Dr. Cohen and his colleagues are focusing on developing therapeutic strategies for multiple sclerosis by taking advantage of mesenchymal stem cells, which offer multiple advantages, including the existence of established experimental approaches to isolate and expand them in culture, but their use is also accompanied by certain challenges. “There is a long list of technical issues that need to be addressed in every experiment,” explains Dr. Cohen.

    While the experience with mesenchymal stem cells has been promising in terms of safety, certain concerns exist regarding potential unanticipated effects. “The approach in our program is to start with a very meticulous safety study and subsequently build upon that,” says Dr. Cohen. Another challenge stems from the paucity of data tracking the administered cells in humans, despite an abundance of results from animal studies showing that transplanted cells survive and reach their intended locations.

    Dr. Cohen and colleagues recently completed the enrollment of 24 participants into a Phase I safety study of autologous mesenchymal stem cells, and no safety concerns were noted. “We plan to proceed with a Phase II study to illustrate the proof of concept for the benefits of this approach, and we also anticipate tracking the administered cells in vivo,” says Dr. Cohen.

  • To the Clinic

    Click Image To Enlarge +
    According to Aastrom Biosciences, its cell-processing system selectively expands mesenchymal cells, monocytes, and alternatively activated macrophages, up to several hundred times more than the number found in the patient’s bone marrow, while retaining many of the hematopoietic cells collected from only a small sample of the patient’s bone marrow.

    “We have developed a highly differentiated product with multiple biological activities that lead to its therapeutic effects,” says Nick Colangelo, president and CEO of Aastrom Biosciences. Colangelo’s firm has developed an approach that is characterized by several distinguishing features. The proprietary automated system that expands (up to 300 times) key cell types collected from a patient’s bone marrow, and the administration of the expanded cells back to the same patient, removing the risk of rejection and eliminating the need for immunosuppressive therapy, are some of the aspects that make this approach unique.

    An additional hallmark of this product lies in its multicellularity. Among several cell types that are incorporated, the CD90+ mesenchymal stromal cells and the CD14+ alternatively activated macrophages are particularly important, due to several sets of activities that account for their therapeutic effects. These cells secrete anti-inflammatory molecules such as IL-10, enzymes involved in extracellular matrix remodeling, and potent angiogenic factors such as VEGF.

    The activities of these cytokines and growth factors are complemented by cell-dependent activities, with macrophages, in particular, modulating the immune response by phagocytizing cellular debris and exerting cardioprotective effects that include oxidized LDL uptake and cholesterol efflux.

    “It is this combination of secreted factors and direct cell activities that leads to the therapeutic effects that we have seen, which involve resolving inflammation, remodeling damaged tissue, and promoting angiogenesis,” Colangelo explains.

    One of Aastrom’s recent efforts is the development of stem cell-based therapeutic approaches for advanced heart failure that develops as a result of ischemic dilated cardiomyopathy (CM). After completing two Phase IIa open-label studies, investigators at Aastrom initiated a 12-month Phase IIb study in 2012.

    “We enrolled our first participants in early April 2013, and treated these patients in the second half of the month,” Colangelo says. Ischemic CM represents one of the most frequent forms of heart failure, and with the scarcity of therapeutic options that are currently available, the development of cellular therapies emerges as a lifesaving approach for this patient group.

  • New Pathways

    We unveiled the role of a previously unrecognized pathway that is important for maintaining the stem cell state,” says Carla M. Koehler, Ph.D., professor of chemistry and biochemistry at the University of California, Los Angeles. In a chemical screen that proposed to identify inhibitors of the mitochondrial FAD-linked sulfhydryl oxidase Erv1, essential for mitochondrial biogenesis and cell survival, Dr. Koehler and her colleagues identified MitoBloCK-6, a small molecule that selectively inhibits the mitochondrial redox-mediated import of Erv1 substrates.

    Despite its ability to inhibit Erv1 and its human homolog ALR in vitro, MitoBloCK-6 did not affect the in vivo growth and function of differentiated cells but, surprisingly, caused apoptosis in pluripotent human embryonic stem cells.

    “When we differentiated stem cells they were no longer susceptible, and when we reprogrammed them to the pluripotent state, they again became susceptible to this compound,” she says.

    MitoBloCK-6 is an attractive option to remove undifferentiated stem cells from differentiated cell populations, and presents multiple advantages over existing protocols. “We are further exploring this compound, and hope that it can be used at a certain time during the differentiation protocol to allow the removal of cells that failed to differentiate, without affecting the ones that became committed to become specific cell types,” Dr. Koehler adds.

    This finding has an additional, more profound significance that extends beyond the field of stem cell biology, as it underscores the cardinal position that basic research plays in advancing translational research.

    “There are so many aspects that we do not understand about the function of many cellular pathways at the basic level, and it is difficult to explore the endpoint without performing and trying to understand the basic research. In this case, we are still trying to understand why mitochondria are important for stem cell survival,” Dr. Koehler says.

    Basic and translational research in stem cell biology and regenerative medicine are witnessing an exciting time. More than 5,000 clinical trials on stem cell therapies are currently under way globally, promising to revolutionize therapeutic prospects. As our knowledge about differentiation and regeneration is advancing, it is essential to appreciate and capitalize on the interdiscliplinary spirit that has become a defining feature of this vibrant and fascinating field.

  • Cell-Based Therapies

    “Having for several decades been at the forefront of the biomanufacturing and bioprocessing of recombinant proteins and monoclonal antibodies, we envision cell therapies as the next wave that is coming along in this market space,” says Firman Ghouze, Ph.D., director of the cell bioprocessing group at GE Healthcare.

    One of the research initiatives at GE Healthcare is directed toward the development of platforms that facilitate the transition toward large-scale applications of such therapies. In the case of cell-based therapies, this involves providing solutions that enable investigators to pursue therapeutic programs in a way that is robust and cost-effective—two important factors to consider, particularly for large clinical trials.

    “We are also trying to build on the scalability,” adds Dr. Ghouze. Significant efforts are being focused toward developing automated and closed systems, which promise multiple benefits, including increased yield, decreased contamination risks, maximal effective use of the manufacturing space, a reduction in the amount of manual work, and the possibility for high-throughput, parallel processing.

    Over the past few years, these have represented some of the key aspects that turned out to be instrumental in the bioprocessing of recombinant proteins. “I can see these considerations becoming important as we develop solutions for cell-based therapies,” explains Dr. Ghouze.

Readers' Comments

Posted 07/03/2013 by Richard Johnson

Out of curiosity, Richard, be very interested in knowing another experts thoughts on the Wired piece. Is it oversimplified?

Posted 07/03/2013 by Mary Staley

It definitely is mind-blowing how varying the answers can be on some of the basic questions for this science.

Posted 06/27/2013 by Dan Wilson

If only all stories about stem cells could include this sort of depth and detail. That's why I like Gen Eng News. A higher standard for reporting on these stories.

Posted 06/26/2013 by Mary Staley

Any recommended resources that explain the different identifying factors of the various types of stem cells ( hematopoietic, mesenchymal, neural, and endothelial stem cells)?

Posted 06/26/2013 by Richard Johnson

Interesting find, Dan. Can't say I’ve ever seen it put into plain terms like it is on Kevin's blog. Easy to digest.

Posted 06/19/2013 by Dan Wilson

I definitely find GEN and Wired to be two of the best sites for following stem cell developments. I especially appreciate the straightforwardness of the pieces on Wired. A great one to check out for the less versed: http://bit.ly/13CXJMJ

Posted 06/19/2013 by Thomas Klein

Yeah, no random uses of the word pluripotency makes this a higher quality article than most. Very keen on the specifics here.

Posted 06/18/2013 by Jenny

Good level of reporting on this. One of the better pieces I've read.

Posted 06/18/2013 by Thomas K

This is why I come to GEN. The reporting is so much more precise. I hate watching other publications butcher findings.

Posted 06/18/2013 by Patrice Bartell

Kyle, here's Richard Stein's reply:
"Research on several types of stem cells, from multiple sources, has seen advances. It would probably create injustice by naming one. Embryonic stem cell research made significant progress, and so have adult stem cell-based approaches. Most exciting, I believe, are the conceptual advances, such as superior strategies to separate cells, or the discovery of new proteins, pathways, and techniques to induce differentiation along specific lineages or reprogramming."

Posted 06/17/2013 by Mary Staley

This is a great perspective on where the research in this field stands.

Posted 06/17/2013 by Kyle Furgeson

Which source of stem cells has our researched most progressed with, Richard?

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