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November 23, 2011

Early data promising for first clinical trial using human cardiac stem cells

by Ben Paylor

A week of highs and lows for the global stem cell community brought with it a healthy dose of optimism for cardiac stem cell researchers. Pilot data from Dr. Roberto Bolli and colleagues’ landmark SCIPIO (Stem Cell Infusion in Patients with Ischemic CardiOmyopathy) clinical trial, published in The Lancet last week, provides much needed new momentum for the therapeutic potential of cardiac stem cells (CSCs).

The data is the first report describing the administration of CSCs in a clinical setting and is based on nearly a decade of preclinical work from Dr. Piero Anversa group, which demonstrated that the heart contains a population of multipotent stem cells capable of contributing to it’s limited regenerative capacity following injury. The research team responsible for the clinical trial, led by Dr. Bolli at the University of Louiseville and Dr. Anversa at Harvard Medical School, demonstrated an unexpected degree of improvements in cardiac function as well as the safety of administering CSCs to patients suffering from heart failure with a previous myocardial infarction.

Nearly 10 years ago, data from Dr. Anversa’s group describing the regenerative effects of bone marrow transplantation in mice with myocardial infarctions prompted a flurry of excitement over the potential of cell therapy to combat a growing global epidemic of cardiovascular disease. Initial excitement was quickly met with skepticism, however, as the capacity of bone marrow-derived cells to directly regenerate the affected heart tissue was cast into doubt following numerous clinical trials reporting modest-at-best functional improvements.

Although clinical trials involving bone marrow-derived cells were not meeting expectations, a growing body of evidence (provided primarily by Dr. Anversa’s group) demonstrated that the heart harbored a tissue-resident population of multipotent stem cells, which could potentially provide a vastly improved cellular source for cell therapy in the damaged myocardium. Further experiments in both small and large animal models strongly supported the notion that transplantation of CSCs into the injured myocardium resulted in significant regeneration and improvement of cardiac function.

Following a report in 2007 describing the presence of CSCs in humans, the stage was set for transplantation of CSCs to be tested clinically. The SCIPIO trial was first approved by the FDA in mid-2008 and, following careful characterization of patients as well rigorous assessment of the regenerative potential of CSCs removed from the patients own hearts during surgery prior to the trial, the first infusion of cardiac stem cells was performed in July of 2009. The recent Lancet report contains early data from the study (still ongoing) and, at the one-year follow-up, describes a 12 per cent improvement in left ventricular ejection fraction (the amount of blood pumped out of the left ventricle) as well significant reduction in the infarct size. Further, reductions in both New York Heart Association functional class and Minnesota Living With Heart Failure Questionnaires score, standard measures of the impact of heart failure on patients quality of life, demonstrated that these improvements were not only seen at the level of organ function. Control patients in the study, who received no treatment, demonstrated no significant improvements in any of the parameters assessed. Importantly, the study also reports no adverse effects in any treated patients, a crucial outcome for any Phase 1 clinical trial.

Dr. Anversa attributes some of the success of the preliminary study to the rigorous cellular characterization during the cell expansion. The CSCs used in the study were obtained from the right atrial appendage of patients undergoing coronary artery bypass grafting and expanded for up to three months following isolation. These cells were assessed for level of commitment, telomere length, telomerase activity, and senescence.

Moving forward, the group plans to apply to conduct a Phase 2/3 clinical trial over the coming years and is understandably optimistic about the future of the study. When asked about the potential for widespread application Dr. Bolli said “We think it will be broadly applicable because Piero Anversa now has shown that he can isolate kit-positive cardiac stem cells from small endocardial biopsies...it’s an outpatient procedure. This really opens the door for widespread application of this therapy to just about everyone with severe heart failure.”

With aging populations in the most of the developed world, increasing prevalence of cardiac disease and lack of appropriate therapies to treat these disorders, there couldn’t be a more opportune time for trials like SCIPIO to demonstrate the potential of cardiac cell therapy.



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Good question Tina - the current hypothesis is that cardiac stem cells (CSCs) will contribute to the natural (and slow) turnover of cardiomyocytes (heart muscle cells) throughout one's life. In situations of injury, CSCs are in fact activated to divide and contribute to regeneration, but their regenerative capacity is quite limited and unable to functionally restore the damaged heart following severe injury (such as an infarction). Additionally, the fate of CSCs present within the infarcted myocardium is comparable to that of other cells present (e.g. cardiomyocytes) in that they will die due by apoptosis and necrosis, preventing them from regenerating these areas. By isolating the cells and then expanding them in the lab, researchers are able to deliver large numbers of these cells to damaged areas of the heart, allowing for substantial regeneration and functional improvements.

An interesting news item. Stem cell research is fast moving forward. As I read on sciencedebate.com, the need for embryonic stem cells is being replaced by the advent of technologies to use adult stem cells and induced pluripotent stem cells. In the case of myocardial problems such as myocardial ischemia etc, what I dont understand is that if there are multipotent tissue residing stem cells in the heart, why are they not naturally activated following the injury.

I'd like to congratulate Prof Anversa and Bolli. Through their positions at Harvard and editor in chief of circ research, they have been able to use their influence to suppress other cpc work in the field. Now that they have finally published in Lancet, they will hopefully allow others to publish new and exciting work.

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