Pharmacologic Intervention for Ectopic Calcification

摘要 该应用程序围绕异位钙化疾病，弹性假黄瘤（PXE）， 婴儿全身性动脉钙化（GACI），两种常染色体隐性遗传疾病， 由于羟基磷灰石钙沉积在皮肤、眼睛和心血管中导致的发病率和死亡率 系统目前还没有有效的或具体的治疗异位钙化在这些疾病。我们 已经为PXE和GACI开发和表征了小鼠模型，这些小鼠现在形成了平台 用于临床前开发这两种目前难以治疗的疾病的治疗策略。的统一 这些异位钙化疾病的病理学发现是血浆无机焦磷酸盐（PPi）减少 程度.虽然在这些疾病中获得了重要的见解，但通过 靶向PPi缺陷防止了新的钙化，但未能去除现有的异位钙化。 在这个建议中，我们将测试总体假设，即抵消异位钙化，无论是通过 预防胎儿中的矿物质沉积和/或在出生后去除现有的沉积物， 临床稳定或治愈PXE或GACI患者的治疗方法治疗药物， 乙酰唑胺，有很大的潜力，抵消异位钙化，主要是由于其物理化学 和不依赖于血浆PPi水平的细胞机制。我们将特别关注两个领域， 研究：（a）通过给予乙酰唑胺预防GACI的产前动脉钙化， 母亲在怀孕期间，有或没有继续治疗的新生儿;这种药物将被重新利用 从其先前的应用程序，以治疗各种钙化疾病;和（B）我们将进一步集中我们的努力， 通过给予乙酰唑胺清除PXE和GACI中存在的钙化。这些研究将利用 预防和清除方法相结合，以对抗异位钙化，提供科学前提， 调查 总的来说，我们提出的研究将提供临床前方法的关键翻译信息 这将允许开发用于目前难治性疾病PXE和GACI的新治疗。我们也期待 我们的研究结果将推进异位钙化的临床管理，可能适用于 一些其他疾病，包括遗传性和获得性疾病。

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.