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Clin Sci (Lond). 2017 Feb 1;131(3):181-195. doi: 10.1042/CS20160378.

In vitro 3D model and miRNA drug delivery to target calcific aortic valve disease.

Author information

1
Center for Excellence in Vascular Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, U.S.A.
2
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, U.S.A.
3
Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
4
Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, U.S.A.
5
Regenerative Medicine Center Utrecht, University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands.
6
Netherlands Heart Institute (ICIN), 3511 EP Utrecht, The Netherlands.
7
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, U.S.A.
8
Center for Excellence in Vascular Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, U.S.A. eaikawa@partners.org.

Abstract

Calcific aortic valve disease (CAVD) is the most prevalent valvular heart disease in the Western population, claiming 17000 deaths per year in the United States and affecting 25% of people older than 65 years of age. Contrary to traditional belief, CAVD is not a passive, degenerative disease but rather a dynamic disease, where initial cellular changes in the valve leaflets progress into fibrotic lesions that induce valve thickening and calcification. Advanced thickening and calcification impair valve function and lead to aortic stenosis (AS). Without intervention, progressive ventricular hypertrophy ensues, which ultimately results in heart failure and death. Currently, aortic valve replacement (AVR), surgical or transcatheter, is the only effective therapy to treat CAVD. However, these costly interventions are often delayed until the late stages of the disease. Nonetheless, 275000 are performed per year worldwide, and this is expected to triple by 2050. Given the current landscape, next-generation therapies for CAVD are needed to improve patient outcome and quality of life. Here, we first provide a background on the aortic valve (AV) and the pathobiology of CAVD as well as highlight current directions and future outlook on the development of functional 3D models of CAVD in vitro We then consider an often-overlooked aspect contributing to CAVD: miRNA (mis)regulation. Therapeutics could potentially normalize miRNA levels in the early stages of the disease and may slow its progression or even reverse calcification. We close with a discussion of strategies that would enable the use of miRNA as a therapeutic for CAVD. This focuses on an overview of controlled delivery technologies for nucleic acid therapeutics to the valve or other target tissues.

KEYWORDS:

3D model; aortic valve; calcification; drug delivery; microRNA (miRNA)

PMID:
28057890
PMCID:
PMC5459552
DOI:
10.1042/CS20160378
[Indexed for MEDLINE]
Free PMC Article

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