Pharmacologic Intervention for Ectopic Calcification

摘要 这项应用围绕异位钙化紊乱、弹性假性黄色瘤(PXE)和 婴儿泛发性动脉钙化(GACI)是两种常染色体隐性遗传病，具有相当大的 皮肤、眼睛和心血管中羟基磷灰石钙沉积的发病率和死亡率 系统。目前，对于这些疾病中的异位钙化，尚无有效或特效的治疗方法。我们 我开发了PXE和GACI的小鼠模型并对其进行了表征，这些小鼠现在形成了平台 为这两种目前难以治愈的疾病制定临床前治疗策略。一元化 这些异位钙化紊乱的病理表现是血浆无机焦磷酸(PPI)降低。 级别。虽然在这些疾病中获得了重要的洞察力，但疾病机制指导的治疗通过 靶向PPI缺乏阻止了新的钙化，但未能消除现有的异位钙化。 在这项提案中，我们将测试整体假设，即通过以下方式对抗异位钙化 防止胎儿中的矿物质沉积和/或在出生后清除现有的矿物质沉积，将提供 临床稳定或治愈的PXE或GACI患者的治疗方法。治疗药物， 乙酰唑胺具有抗异位钙化的巨大潜力，这主要是由于它的物理化学作用。 以及独立于血浆PPI水平的细胞机制。我们将特别关注以下两个领域 研究：(A)使用乙酰唑胺预防GACI中的产前动脉钙化 怀孕期间的母亲，无论是否继续治疗新生儿；这种药物将被重新调整用途 从以前应用于治疗各种钙化疾病；及(B)我们将进一步集中力量 用乙酰唑胺清除PXE和GACI中现有的钙化。这些研究将利用 联合防治和清除方法中和异位钙化，提供科学的前提 这项调查。 总的来说，我们建议的研究将提供临床前方法的关键翻译信息。 这将为目前难以治愈的PXE和GACI疾病开发新的治疗方法。我们也期待着 我们的发现将促进异位钙化的临床治疗，可能适用于 其他疾病的数量，包括遗传病和获得性疾病。

ABSTRACT This application revolves around ectopic calcification disorders, pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI), two autosomal recessive diseases with considerable morbidity and mortality due to calcium hydroxyapatite deposition in the skin, eyes, and the cardiovascular system. There is currently no effective or specific treatment for the ectopic calcification in these disorders. We have developed and characterized mouse models for both PXE and GACI, and these mice now form the platform for preclinical development of therapeutic strategies for these two, currently intractable conditions. The unifying pathological finding in these ectopic calcification disorders is reduced plasma inorganic pyrophosphate (PPi) levels. While significant insight was gained in these disorders, disease mechanism-directed treatment by targeting PPi deficiency prevented new calcification but failed to remove existing ectopic calcification. In this proposal, we will test the overall hypothesis that counteracting ectopic calcification, either by prevention of mineral deposition in the fetus and/or removal of the existing deposits postnatally, will provide treatment approaches with clinical stabilization or cure for patients with PXE or GACI. The therapeutic drug, acetazolamide, has the great potential of counteracting ectopic calcification, primarily due to its physicochemical and cellular mechanisms which are independent of plasma PPi levels. We will specifically focus on two areas of investigation: (a) Prevention of prenatal arterial calcification in GACI by administration of acetazolamide to the mothers during pregnancy, with or without continued treatment of the newborns; this drug will be repurposed from its previous applications to treat various calcification disorders; and (b) We will further focus our efforts to remove existing calcification in PXE and GACI by administration of acetazolamide. These studies will utilize combined prevention and removal approaches to counteract ectopic calcification, providing scientific premise to the investigation. Collectively, our proposed studies will provide critical translational information from preclinical approaches that will allow development of novel treatment for currently intractable disorders PXE and GACI. We also expect that our findings will advance clinical management of ectopic calcification in general, potentially applicable to a number of other diseases, both genetic and acquired.