Identifying therapeutic strategies for the multisystem genetic disorder Pseudoxanthoma Elasticum

摘要 异位钙化是一种以软组织矿化为特征的病理过程。 弹性纤维假黄瘤（Pseudoxanthoma Elasticum，PXE）是一种常染色体隐性遗传病， 眼睛、皮肤、心脏和血管的异位钙化，并伴有毁灭性的临床后遗症 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 虽然ABCC 6已被确定为致病基因，但目前还不存在任何治疗方法。 PXE。在本申请中，我们鉴定了一种新的分子靶标ENPP 1（外核苷酸-焦磷酸酶1）， PXE中钙化的关键介质。我们证明ENPP 1在钙化的心肌细胞中显著上调， 组织中的PXE和改变焦磷酸盐/磷酸盐平衡，创造一个允许的环境， 发生钙化。我们已经创建了针对ENPP 1的小分子和单克隆抗体， 证明了这些药物在预防PXE钙化中的作用。使用小鼠PXE模型，沿着 利用人多能干细胞模型的PXE，我们研究了 ENPP 1-PPi-Pi轴介导PXE中的钙化并鉴定用于治疗的新型药理学试剂 这种无法治愈的疾病。如果成功的话，我们的建议可能会直接导致新的治疗方法的确定。 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.