Identifying therapeutic strategies for the multisystem genetic disorder Pseudoxanthoma Elasticum

摘要 异位钙化代表以软组织矿化为特征的病理过程。 弹性假黄瘤 (PXE) 是一种常染色体隐性遗传病，其特征为进行性进展 眼睛、皮肤、心脏和血管的异位钙化，并与毁灭性的临床后遗症相关 例如失明、猝死和伤口愈合不良等皮肤问题。 PXE是一种孤儿病 尽管ABCC6已被确定为致病基因，但目前尚无任何治疗方法 PXE。在此应用中，我们确定了一个新的分子靶标 ENPP1（外核苷酸焦磷酸酶 1）作为 PXE 中钙化的关键介质。我们证明 ENPP1 在钙化中显着上调 PXE 中的组织并改变焦磷酸盐/磷酸盐平衡，为 发生钙化。我们已经创建了针对 ENPP1 和 证明这些药物在防止 PXE 钙化方面的作用。使用 PXE 小鼠模型 通过 PXE 的人类多能干细胞模型，我们研究了 PXE 的分子和生化作用 ENPP1-PPi-Pi 轴介导 PXE 钙化并确定新的治疗药物 这种无法治愈的疾病。如果成功，我们的建议可能会直接导致新疗法的确定 PXE 策略。

Abstract Ectopic calcification represents a pathologic process characterized by mineralization of soft tissues. Pseudoxanthoma Elasticum (PXE) is an autosomal recessive genetic disorder characterized by progressive ectopic calcification of the eyes, skin heart and blood vessels and associated with devastating clinical sequelae such as blindness, sudden death and skin problems such as poor wound healing. PXE is an orphan disease and though ABCC6 has been identified as the causative gene, there currently do not exist any therapies for PXE. In this application we identify a novel molecular target, ENPP1 (ectonucleotide-pyrophosphatase 1) as a critical mediator of calcification in PXE. We demonstrate that ENPP1 is dramatically upregulated in calcific tissues in PXE and alters the pyrophosphate/phosphate balance to create a permissive environment for calcification to occur. We have created small molecules and monoclonal antibodies targeting ENPP1 and demonstrate the role of these agents in preventing calcification in PXE. Using murine models of PXE along with human pluripotent stem cell modeling of PXE, we investigate the molecular and biochemical role of ENPP1-PPi-Pi axis in mediating calcification in PXE and identify novel pharmacologic agents for the treatment of this incurable disorder. If successful, our proposal may lead directly to the identification of novel therapeutic strategies for PXE.