Editors' ChoiceCardiovascular Disease

Slow and steady wins the race

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Science Translational Medicine  16 May 2018:
Vol. 10, Issue 441, eaat8530
DOI: 10.1126/scitranslmed.aat8530

Abstract

A biomaterial-based approach to sustained delivery of therapeutic extracellular vesicles leads to cardiac recovery after myocardial infarction in rats.

As taught by Aesop’s fable “The Tortoise and the Hare,” slow and steady activity is sometimes preferable to immediate but brief action. Researchers in the field of sustained-release drug delivery have applied this lesson, focusing on developing methods to prolong the effects of a single administration of therapeutic agents, such as small molecule drugs, nucleic acids, and proteins. In their recent work, Liu et al. extended this concept of sustained release to an emerging class of biotherapeutics: extracellular vesicles (EVs).

EVs are membranous cell-derived products that have bioactive properties dictated by their cells of origin. Recent interest in the therapeutic use of EVs has led to testing in large animal models of myocardial infarction, stroke, traumatic brain injury, acute lung injury, and other diseases and injuries. However, the specific delivery modality and schedule most suitable for maximizing the effects of EVs remains unknown. In many animal models, EVs are serially injected to increase their therapeutic impact. However, this approach is not well-suited for clinical translation. Thus, Liu et al. examined the efficacy of a collagen hydrogel supported by a gelatin-based mesh (GELFOAM) to prolong the delivery of EVs isolated from human induced pluripotent stem cell–derived cardiomyocytes (iCM) in a rat model of acute myocardial infarction. Instead of a single bolus injection, encapsulation in hydrogel allowed for the release of iCM EVs over about 3 weeks. iCM EVs released from gel patches were functional, nonarrhythmogenic, and more effectively promoted cardiac recovery than gel patches containing EVs from undifferentiated induced pluripotent stem cells. The study also showed that iCM EVs are enriched in cardiac-specific microRNAs that may be responsible for the therapeutic effects observed.

Overall, this report establishes the integration of controlled release strategies and technology into EV therapies. Direct comparisons between sustained EV delivery and bolus injection still need to be made, and the potential of different EV delivery vehicles and release kinetics remains to be elucidated. However, the concept introduced here promises to expand the translational potential of EV treatments for a vast variety of diseases and injuries.

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