异位钙化症动脉病变的未来治疗方法

Benjamin M. Davies, F. Rutsch, Naren Vyavahare, Alexander Jones
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摘要

异位钙化症(包括婴儿全身动脉钙化症(GACI)和假黄疽弹性瘤)虽然罕见,但对个人、医疗保健和社会都有很大影响,相关的发病率、死亡率和医疗保健成本都很高。现有的治疗方法无法根治,只能通过减少细胞外钙化来限制动脉病变的发展,而动脉病变是大部分发病率的罪魁祸首,就 GACI 而言,早期死亡率很高(婴儿期约为 50%)。本文对当前和新兴的医疗方法进行了回顾和评论,包括饮食调节、磷酸盐结合剂、双磷酸盐、组织非特异性碱性磷酸酶抑制剂、外显子核苷酸焦磷酸酶/磷酸二酯酶 1 (ENPP1) 酶替代、等位基因特异性疗法、基因疗法和抗体靶向治疗。现有的疗法可以限制动脉钙化的进一步发展,但特别是在 GACI 患者中,出生时就可能出现明显的钙化,导致婴儿死亡率居高不下。这就凸显了对旨在逆转已形成的钙化而不仅仅是减缓其进展的新方法的需求。最近,出现了一种很有前景的新型抗体靶向纳米粒子疗法,它可以逆转动物体内已形成的动脉钙化,恢复动脉弹性。在一种实现方式中,纳米粒子携带乙二胺四乙酸二钠盐等螯合剂到达动脉损伤部位,将螯合剂的作用集中在需要的地方,并限制脱靶效应。这类药物将补充现有和新出现的疗法,如ENPP1酶替代疗法,这些疗法可减缓或防止钙化的进展,为异位钙化症患者的动脉健康提供了 "重置 "的机会。目前,异位钙化症很难得到有效治疗,发病率和死亡率都很高,尤其是在 GACI 中。最近的药物研发成果让我们有理由对新时代的有效疗法充满希望,这种疗法可能会逆转已形成的动脉疾病并阻止其发展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Future treatments for the arteriopathy of ectopic calcification disorders
Ectopic calcification disorders, including Generalized Arterial Calcification of Infancy (GACI) and Pseudoxanthoma Elasticum are rare but impactful on individuals, healthcare and society, with significant associated morbidity, mortality and healthcare costs. Available therapies are not curative and focus on reducing extracellular calcification to limit progression of the arteriopathy that is responsible for much of the morbidity and, in the case of GACI, significant early mortality (approximately 50% in infancy). In this article, current and emerging medical approaches are reviewed and critiqued, including dietary manipulation, phosphate binders, bisphosphonates, tissue nonspecific alkaline phosphatase inhibitors, ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) enzyme replacement, allele-specific therapies, gene therapies, and antibody targeted treatment. Available therapies may limit further arterial calcification, but in GACI in particular, significant calcification can be present at birth, contributing to high infant mortality. This highlights the need for new approaches that aim to reverse established calcification, rather than merely slow its progression. Recently, a promising new class of antibody-targeted nanoparticle therapeutics has emerged that can reverse established arterial calcification in animals, restoring arterial elasticity. In one realization, nanoparticles carry established chelators, such as ethylenediaminetetraacetic disodium acid, to sites of arterial damage, concentrating the impact of the chelator where it is needed and limiting off-target effects. Such drugs would complement existing and emerging therapies, such as ENPP1 enzyme replacement, that slow or prevent progression of calcification, by offering an opportunity to “reset” arterial health in ectopic calcification disorders. At present, ectopic calcification disorders are challenging to treat effectively and carry a high burden of morbidity and mortality, particularly in GACI. Recent drug developments offer good reason to be hopeful for a new era of effective therapeutics that may reverse established arterial disease as well as halt its progression.
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