Pseudoxanthoma elasticum (PXE) is a genetic multisystem ectopic calcification disorder caused by inactivating mutations in the ABCC6 gene encoding ABCC6, a hepatic efflux transporter. ABCC6-mediated ATP secretion by the liver is the main source of a potent endogenous calcification inhibitor, plasma inorganic pyrophosphate (PPi); the deficiency of plasma PPi underpins PXE. Recent studies demonstrated that INZ-701, a recombinant human ENPP1 that generates PPi and is now in clinical trials, restored plasma PPi levels and prevented ectopic calcification in the muzzle skin of Abcc6−/−mice. This study examined the pharmacokinetics, pharmacodynamics, and potency of a new ENPP1-Fc isoform, BL-1118, in Abcc6−/− mice. When Abcc6−/− mice received a single subcutaneous injection of BL-1118 at 0.25, 0.5, or 1 mg/kg, they had dose-dependent elevations in plasma ENPP1 enzyme activity and PPi levels, with an enzyme half-life of approximately 100 h. When Abcc6−/− mice were injected weekly from 5 to 15 weeks of age, BL-1118 dose-dependently increased steady-state plasma ENPP1 activity and PPi levels and significantly reduced ectopic calcification in the muzzle skin and kidneys. These results suggest that BL-1118 is a promising second generation enzyme therapy for PXE, the first generation of which is currently in clinical testing.

中文翻译：

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PXE 的新疗法：重组 ENPP1 酶疗法


弹性假黄瘤 （PXE） 是一种遗传性多系统异位钙化疾病，由编码 ABCC6（一种肝脏外排转运蛋白）的 ABCC6 基因突变失活引起。肝脏分泌 ABCC6 介导的 ATP 是强效内源性钙化抑制剂血浆无机焦磷酸盐 （PPi） 的主要来源;血浆 PPi 的缺乏是 PXE 的基础。最近的研究表明，INZ-701 是一种产生 PPi 的重组人 ENPP1，目前正在进行临床试验，可恢复血浆 PPi 水平并防止 Abcc6−/−小鼠口部皮肤的异位钙化。本研究在 Abcc6 - / - 小鼠中检查了新的 ENPP1-Fc 亚型 BL-1118 的药代动力学、药效学和效价。当 Abcc6 - / - 小鼠以 0.25、0.5 或 1 mg/kg 的单次皮下注射 BL-1118 时，它们的血浆 ENPP1 酶活性和 PPi 水平呈剂量依赖性升高，酶半衰期约为 100 小时。当 5 至 15 周龄每周注射 Abcc6 - / - 小鼠时，BL-1118 剂量依赖性地增加稳态血浆 ENPP1 活性和 PPi 水平，并显着减少口吻皮肤和肾脏的异位钙化。这些结果表明，BL-1118 是一种很有前途的第二代 PXE 酶疗法，其中第一代目前正在临床试验中。