In vitro 3D model and miRNA drug delivery to target calcific aortic valve disease.
In vitro 3D model and miRNA drug delivery to target calcific aortic valve disease.
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DOI：
10.1042/cs20160378
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发表时间：
2017-02-01
期刊：
影响因子：
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通讯作者：
Aikawa E
中科院分区：
文献类型：
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作者：
van der Ven CF;Wu PJ;Tibbitt MW;van Mil A;Sluijter JP;Langer R;Aikawa E
钙化性主动脉瓣疾病（CAVD）是西方人群中最常见的心脏瓣膜病，在美国每年有17000人死亡，25%的65岁以上的老年人受到影响。与传统观点相反，CAVD不是一种被动的退行性疾病，而是一种动态疾病，其中瓣叶中的初始细胞变化进展为纤维化病变，从而诱导瓣膜增厚和钙化。晚期增厚和钙化损害瓣膜功能并导致主动脉瓣狭窄（AS）。如果不进行干预，进行性心室肥厚会加重，最终导致心力衰竭和死亡。目前，主动脉瓣置换术（AVR），手术或经导管，是唯一有效的治疗CAVD。然而，这些昂贵的干预措施往往被推迟到疾病的晚期。尽管如此，全世界每年仍有275000例手术，预计到2050年将增加两倍。鉴于目前的情况，需要下一代CAVD疗法来改善患者的预后和生活质量。在这里，我们首先提供了一个背景的主动脉瓣（AV）和CAVD的病理生物学，以及突出当前的方向和未来的展望，在体外CAVD的功能三维模型的发展。然后，我们考虑一个经常被忽视的方面有助于CAVD：miRNA（错误）调节。治疗可能在疾病的早期阶段使miRNA水平正常化，并可能减缓其进展甚至逆转钙化。最后，我们讨论了能够使用miRNA作为CAVD治疗剂的策略。这集中在瓣膜或其他靶组织的核酸治疗剂的受控递送技术的概述。
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.