Novel Treatments for PXE

摘要 这一应用主要集中在可遗传异位矿化的原型--弹性假黄瘤(PXE)上 精神错乱。PXE是由编码ABCC6的ABCC6基因突变引起的，ABCC6是一种外排转运蛋白 主要在肝脏表达。典型的临床表现包括皮肤表现，这意味着 可能出现导致视力丧失和失明的眼部并发症，以及 心血管受累，包括肾源性高血压、间歇性跛行、 胃肠道动脉，早期心肌梗死和中风。PXE尚无特效或有效的治疗方法 或相关的异位矿化障碍。最近在理解这一问题上取得了重大进展 导致PXE中异位矿化的病理机制细节，这一信息现在提供了一个 开发新疗法的平台。我们最近观察到的一个特别耐人寻味的现象是 从肝细胞到循环的ATP依赖于功能ABCC6，在缺乏ABCC6的情况下 活动性，如在PXE中，血浆PPI水平明显降低。由于PPI是一种强大的抗矿化剂 因素，降低的血浆PPI水平，特别是降低的PPI/PI比率允许异位矿化 随之而来的是周围组织。在这项研究中，我们将检验统一的假设，即恢复血浆PPI PXE患者体内的水平将抵消这种毁灭性疾病的临床表现。为了增强 血浆PPI水平，我们制定了三个具体目标，建议：(A)药物促进释放 以ABCC6依赖或ABCC6非依赖的方式抑制细胞ATP；(B)抑制组织非 特异性碱性磷酸酶(TNAP)，负责将血浆PPI降解为PI的酶；和(C)口服 给予PPI，随后血浆PPI水平升高。这些计划是基于Solid 初步数据，他们利用开发和开发的具有良好特性的小鼠和大鼠模型 我们实验室的特点，概述了临床，组织病理学，超微结构和遗传学特征 PXE.我们的计划还包括一项I期临床试验，以展示口服PPI在 人体志愿者和PXE患者的血浆药代动力学测定。 总的来说，我们利用PXE体内模型系统进行的最先进的研究有望提供 PXE患者恢复血浆PPI水平的潜在疗效的关键临床前信息，以及随后的 抑制异位成矿作用。有理由认为，这些信息将对发展有用。 对PXE以及其他异位矿化障碍的药物治疗，对这些疾病没有 目前已有有效或特效的治疗方法。

ABSTRACT This application focuses on pseudoxanthoma elasticum (PXE), a prototype of heritable ectopic mineralization disorders. PXE is caused by mutations in the ABCC6 gene which encodes ABCC6, an efflux transporter expressed primarily in the liver. Characteristic clinical manifestations include cutaneous findings which signify the potential for development of ocular complications leading to loss of visual acuity and blindness, as well as cardiovascular involvement, including nephrogenic hypertension, intermittent claudication, bleeding from gastrointestinal arteries, early myocardial infarct and stroke. There is no specific or effective treatment for PXE or related ectopic mineralization disorders. Significant recent progress has been made in understanding the pathomechanistic details resulting in ectopic mineralization in PXE, and this information has now provided a platform to develop novel treatments. A particularly intriguing recent observation made by us is that release of ATP from hepatocytes to the circulation is dependent on functional ABCC6, and in the absence of ABCC6 activity, as in PXE, the plasma PPi levels are markedly reduced. Since PPi is a powerful anti-mineralization factor, reduced plasma PPi levels and particularly reduced PPi/Pi ratio allow ectopic mineralization in the peripheral tissues to ensue. In this study, we will test the unifying hypothesis that restoration of plasma PPi levels in patients with PXE will counteract the clinical manifestations of this devastating disease. To enhance plasma PPi levels, we have developed three Specific Aims proposing (a) pharmacologically enhanced release of cellular ATP either in an ABCC6-dependent or ABCC6-independent manner; (b) inhibition of tissue non- specific alkaline phosphatase (TNAP), the enzyme responsible for degradation of plasma PPi to Pi; and (c) oral administration of PPi with subsequent increases in plasma PPi levels. These plans are based on solid preliminary data, and they take advantage of well-characterized mouse and rat models developed and characterized in our laboratory, recapitulating clinical, histopathologic, ultrastructural and genetic features of PXE. Our plans also include a Phase I Clinical Trial to demonstrate the absorption of orally administered PPi in human volunteers and in patients with PXE with assay of pharmacokinetics in plasma. Collectively, our state-of-the-art studies utilizing in vivo model systems for PXE are expected to provide critical preclinical information of potential efficacy to restore plasma PPi levels in PXE, with subsequent inhibition of ectopic mineralization. Such information is reasonably expected to be useful towards development of pharmacologic treatments for PXE, as well as for other ectopic mineralization disorders, for which no effective or specific therapy is currently available.