“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
“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.
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.