Therapy for ectopic calcification in pseudoxanthoma elasticum

弹性纤维性假黄瘤异位钙化的治疗 摘要 弹性假黄瘤（PXE）是一种罕见的单基因疾病，导致眼睛的异位钙化， 皮肤和脉管系统。PXE由ABCC 6基因的功能丧失突变引起。一般来说，ABCC 6 将ATP从肝脏转运到循环中，然后转化为腺苷酸（AMP） 和无机焦磷酸盐（PPi）通过酶外核苷酸焦磷酸酶/磷酸二酯酶-1 （ENPP 1）。循环中的PPi是异位钙化的有效抑制剂;它拮抗无机钙的能力， 磷酸盐与钙结晶形成羟基磷灰石。患有PXE的患者比正常人减少70%， PPi的循环水平，导致迟发性全身钙化。PPi替代治疗 由于半衰期短和不能口服的错误观念， 最近，我们已经开发了一种专有的胃释放盐形式的PPi口服给药， 在小鼠和人类中循环PPi的临床有意义的增加。在ABCC 6-/-小鼠中经口递送PPi 减弱钙化并建立概念验证。在第一阶段，我们将 药代动力学和毒理学研究，然后在PXE动物模型中评估Lys-PPi。第二阶段工作 将包括IND赋能研究，最终提交IND。这项工作的成功结果将 为PXE和其他异常异位妊娠疾病提供专有的基于机制的一流疗法 钙化

Therapy for ectopic calcification in pseudoxanthoma elasticum Abstract Pseudoxanthoma elasticum (PXE) is a rare monogenic disease that leads to ectopic calcification of the eyes, skin, and vasculature. PXE results from loss-of-function mutations in the ABCC6 gene. Normally, ABCC6 transports ATP from the liver into circulation where it is then converted into adenosine monophosphate (AMP) and inorganic pyrophosphate (PPi) by the enzyme Ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1). PPi in circulation is a potent inhibitor of ectopic calcification; it antagonizes the ability of inorganic phosphate to crystallize with calcium to form hydroxyapatite. Patients with PXE have a 70% reduction of normal circulating levels of PPi which results in late-onset generalized systemic calcification. PPi replacement therapy has been challenging given the short half-life and misconceived notion that it could not be delivered orally. Recently, we have developed a proprietary gastric-release salt form of PPi for oral administration that achieves clinically meaningful increases in circulating PPi in mice and in humans. Orally delivered PPi in ABCC6-/- mice attenuates calcification and establishes proof-of-concept. In this Phase 1 project, we will conduct pharmacokinetic and toxicology studies and then evaluate Lys-PPi in an animal model of PXE. Phase 2 work will comprise IND-enabling studies, culminating in the filing of an IND. A successful outcome of this work will provide a proprietary mechanism-based first-in-class therapy for PXE and other disorders of abnormal ectopic calcification.