Just over two years ago I wrote about early reports from Dr. Roberto Bolli et al.’s SCIPIO trial running out of the University of Louisville in collaboration with the Harvard Medical School. Since this time, much has happened in the realm of cell therapy to treat ischemic cardiomyopathy and I was able to get an update on the state of the field at the World Stem Cell Summit in San Diego yesterday.
The session began with a somewhat sobering look at the trials and tribulations of this field of research over the past 10 years. Dr. Stephen Epstein provided a critical perspective on the preponderance of cardiac regenerative clinical trials that he described as “inconsistent at best, disappointing at worst.”
We now know that the application of bone-marrow derived cells (summarized in a recent Cochrane Review) provide only “moderate improvement” over standard treatments) and the large expectations of researchers has recently fallen on the shoulders of a new group of trials applying cardiac-derived stem/progenitor cells. Unfortunately, these expectations continue to be unmet.
This was showcased by recent results from the CADUCEUS (CArdiosphere-Derived aUtologous stem Cells) clinical trial launched in the spring of 2012 by Dr. Eduardo Marban, shortly after the aforementioned SCIPIO trial. Although the results were encouraging in regards to several indexes of cardiac regeneration (e.g. reduction of scar size, viable myocardium), the study’s authors reported no improvements in NYHA functional class or quality of life scores. (On a historical side note I would be remiss not to point out: the staff of Caduceus has long been mistakenly used as a symbol of medicine, which it is not. The proper Greek reference is the staff of Asclepius that has one coiled snake around the staff rather than two. The staff of Caduceus was wielded by Hermes, the patron of merchants, and is a symbol of commerce not medicine, perhaps an early indication of the ultimate outcome of this trial.)
The session addressed several key questions that were articulated in a recent Cell Stem Cell review, and an important distinction was made between strategies that use autologous and allogenic cell sources. Given our growing understanding of declines in stem cell function with age, it would come as no surprise that clinical trials utilizing autologous cells derived from middle-aged and elderly patients (average age in the CADUCEUS trial was early 50s) were not meeting the lofty expectations of the field. One of the speakers, Dr. Karl-Henrik Grinnemo, outlined how allogenic cell strategies utilizes younger sources can provide an improved capacity to migrate to damage tissue as well as increased regenerative capacity, and may be where we need to focus our future efforts if cell therapy is to live up to its much lauded potential in regenerating damaged hearts.
Although not mentioned at the session, one cannot discuss the current state of cardiac regenerative medicine without mention of the exciting work being done on in vivo cardiac transdifferentiation. Following pioneering work by Deepak Srivastava’s group at the Gladstone Institutes, numerous groups have demonstrated experimentally that cardiac regeneration can be accomplished by direct reprogramming of cardiac fibroblasts into cardiomyocytes. Problems such as low efficiency and incomplete efficacy of reprogramming still need to be dealt with before clinical translation can proceed, but it is expected that as a deeper understanding of the molecular mechanisms grows so too will the value of this novel regenerative strategy.
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