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A mechanistic roadmap for the clinical application of cardiac cell therapies

Abstract

The development of cells for regenerative therapy has encountered many pitfalls on its path to clinical translation. In cardiology, clinical studies of heart-targeted cell therapies began two decades ago, yet progress towards reaching an approved product has been slow. In this Perspective, I provide an overview of recent cardiac cell therapies, with a focus on the hurdles limiting the translation of cell products from research laboratories to clinical practice. By focusing on heart failure as a target indication, I argue that strategies for overcoming limitations in clinical translation require an increasing emphasis on mechanism-supported efficacy, rather than on phenomenological observations. As research progresses from cells to paracrine mechanisms to defined factors, identifying those defined factors that are involved in achieving superior therapeutic efficacy will better inform the use of cells as therapeutic candidates. The next generation of cell-free biologics may provide the benefits of cell therapy without the intrinsic limitations of whole-cell products.

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Fig. 1: Biological processes modulated by cell therapy.
Fig. 2: Clinical testing of cell therapies for heart disease.
Fig. 3: Obstacles in the translation of cell therapy, from proof of concept through to product approval.
Fig. 4: CDC properties.
Fig. 5: Changes from canonical to indirect (paracrine) mechanisms of action of cell therapy.
Fig. 6: Exosome biology and evidence of exosome efficacy.
Fig. 7: Defined exosome contents implicated in CDC-mediated cardioprotection.

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Acknowledgements

This work is supported by grants from the National Institutes of Health, the California Institute for Regenerative Medicine, the United States Department of Defense, and Coalition Duchenne. I thank A. Ibrahim for creating a first draft of Fig. 6a, and L. Marbán for a critical reading of the manuscript and for helpful suggestions.

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E.M. holds founder’s equity in, and serves as unpaid scientific advisor to, Capricor Inc.

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Marbán, E. A mechanistic roadmap for the clinical application of cardiac cell therapies. Nat Biomed Eng 2, 353–361 (2018). https://doi.org/10.1038/s41551-018-0216-z

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