Symposium on regenerative medicine
Breakthroughs in Cell Therapy for Heart Disease: Focus on Cardiosphere-Derived Cells

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Abstract

The clinical reality of cell therapy for heart disease dates back to the 1990s, when autologous skeletal myoblasts were first transplanted into failing hearts during open-chest surgery. Since then, the focus has shifted to bone marrow–derived cells and, more recently, cells extracted from the heart itself. Although progress has been nonlinear and often disheartening, the field has nevertheless made remarkable progress. Six major breakthroughs are notable: (1) the establishment of safety with intracoronary delivery; (2) the finding that therapeutic regeneration is possible; (3) the increase in allogeneic cell therapy; (4) the effect of increasing mechanistic insights; (5) glimmers of clinical efficacy; and (6) the progression to phase 2 and 3 studies. This article individually reviews these landmark developments in detail and concludes that the field has reached a new phase of maturity where the prospect of clinical impact is increasingly imminent.

Section snippets

Breakthrough 1: Establishment of Safety With Intracoronary Delivery

Skeletal myoblasts were the first cells to be applied to heart disease, on the logical premise that autologous satellite cells might develop into mature contractile units when implanted ectopically into the diseased heart.6 The paradigm involved harvesting skeletal muscle biopsy specimens from patients with HF who were to undergo elective cardiac surgery; myoblasts would be grown ex vivo and then reimplanted by direct intramyocardial injection at the time of surgery. Despite early enthusiasm

Breakthrough 2: Finding of Therapeutic Regeneration

Regeneration is defined as “regrowth of lost or destroyed parts or organs.”19 Although human BMMC studies have reported reductions in scar size,20 the effect is solely on scar mass with no reciprocal increase in viable myocardium. Thus, such changes report a decrease in the extent of injury but not regrowth of destroyed parts. During the past 10 years, my laboratory has developed cardiosphere-derived cells (CDCs) as a candidate cell type for regenerative therapy after MI.21 These heart-derived

Breakthrough 3: The Rise of Allogeneic Cell Therapy

During the first decade of cell therapy for heart disease, most clinical trials were conducted using autologous cells. This approach has the advantage that it avoids immunologic rejection, but autologous therapy requires patient-specific tissue harvesting, cell processing, and quality control, imposing significant risk, expense, and inflexibility with regard to the timing of treatment. In addition, cell efficacy may vary with donor age and comorbidities. The use of allogeneic cells, if safe and

Breakthrough 4: Increasing Mechanistic Insights

The guiding principle underlying the use of stem cells to achieve regeneration is the idea that injected cells will engraft, proliferate, and differentiate, thereby repopulating the injured heart. However, in many published studies, cell transplantation produces beneficial effects despite poor retention and minimal long-term survival of transplanted cells.31 How can transient, paltry short-term cell survival suffice to produce lasting benefits? Multiple lines of evidence now indicate that most

Breakthrough 5: Glimmers of Clinical Efficacy

The BMMC experience has been notable for little evidence of benefit in surrogate end points, namely, an inconsistency of improvements in ejection fraction and scar size and the absence of rigorous evidence of genuine myocardial regeneration. Nevertheless, it is intriguing that significant benefits on clinical end points have been reported. The Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction study reported favorable clinical outcomes associated with

Breakthrough 6: Progression to Phase 2 and 3 Studies

All too often in cell therapy, as in many other fields, promising early-phase trial results fail to be confirmed in larger studies.51 Well-powered and rigorously designed (randomized, placebo-controlled, double-blind) large-scale clinical trials with long-term follow-up, focusing on hard clinical end points, are mandatory to determine whether the changes in surrogate end points (eg, scar size, ventricular volumes, and ejection fraction) are consistent and whether they translate into increased

Conclusion

In the past several years, we have progressed from a profusion of hype to the point of having a solid basis for moving forward. With the good fortune of prevalent safety to date, we have managed to avoid the sort of debacle that derailed gene therapy for more than a decade.53 The evidence that therapeutic regeneration is possible, in a setting where conventional wisdom teaches that scar is irreversible, catapults the field onto a new plane yet to be achieved by any other treatment approach. The

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  • Cited by (0)

    Grant Support: Work in Dr Marbán’s laboratory is funded by National Institute of Health grant R01 HL083109, US Department of Defense grant CSR205330/221349, and California Institute for Regenerative Medicine grant RB4-06215.

    Potential Competing Interests: Dr Marbán is founder of, is unpaid adviser to, and owns equity in Capricor Therapeutics.

    Individual reprints of this article and a bound reprint of the entire Symposium on Regenerative Medicine will be available for purchase from our website www.mayoclinicproceedings.org.

    The Symposium on Regenerative Medicine will continue in an upcoming issue.

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