Cheng Zhiliang, O'Brien Kevin, Howe Jennifer, Sullivan Caitlin, Schrier Denis, Lynch Angela, Jungles Steven, Sabbagh Yves, Thompson David
Inozyme Pharma, Boston, MA, USA.
J Bone Miner Res. 2021 Aug;36(8):1594-1604. doi: 10.1002/jbmr.4315. Epub 2021 May 5.
Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the major enzyme that cleaves extracellular adenosine triphosphate (ATP) to generate pyrophosphate (PPi), an inorganic metabolite with potent anticalcification activity. Loss-of-function mutations cause hypopyrophosphatemia and lead to a state of ENPP1 deficiency, which has an acute infantile phase known as generalized arterial calcification of infancy (GACI) and a pediatric to adult phase known as autosomal-recessive hypophosphatemic rickets type 2 (ARHR2). ENPP1 deficiency manifests as ectopic calcification of multiple tissues, neointimal proliferation, premature mortality, impaired growth, and bone deformities. INZ-701, a human ENPP1-Fc protein, is in clinical development as an enzyme replacement therapy for the treatment of ENPP1 deficiency. The pharmacokinetic and pharmacodynamic profile and therapeutic effect of INZ-701 were investigated in Enpp1 mice, a murine model of ENPP1 deficiency. Enpp1 mice have undetectable plasma PPi, lower plasma phosphate, and higher FGF23 levels compared with wild-type (WT) mice. Enpp1 mice on the acceleration diet, containing high phosphate and low magnesium, quickly develop clinical signs, including dehydration, rough hair coat, pinned ears, stiffed legs, and hunched back. Enpp1 mice treated with vehicle had aforementioned clinical signs plus severe ectopic calcification in multiple tissues and bone defects, characteristics of the clinical phenotype observed in GACI and ARHR2 patients. Our results showed a durable PPi response for more than 3 days after a single dose of INZ-701. Treatment of ENPP1-deficient mice every other day with INZ-701 for 8 weeks restored circulating levels of PPi, prevented pathological calcification in all the tested organs, restored growth parameters, corrected bone defects, improved clinical signs, and decreased mortality in Enpp1 mice, demonstrating the potential of INZ-701 to treat ENPP1 deficiency. © 2021 American Society for Bone and Mineral Research (ASBMR).
胞外核苷酸焦磷酸酶/磷酸二酯酶1（ENPP1）是将细胞外三磷酸腺苷（ATP）裂解生成焦磷酸（PPi）的主要酶，PPi是一种具有强大抗钙化活性的无机代谢物。功能丧失突变会导致低焦磷酸血症，并导致ENPP1缺乏状态，其具有一个被称为婴儿期全身性动脉钙化（GACI）的急性婴儿期阶段以及一个从儿童期到成人期的阶段，即2型常染色体隐性低磷性佝偻病（ARHR2）。ENPP1缺乏表现为多个组织的异位钙化、新生内膜增殖、过早死亡、生长受损以及骨骼畸形。INZ - 701是一种人ENPP1 - Fc蛋白，作为治疗ENPP1缺乏的酶替代疗法正处于临床开发阶段。在ENPP1缺乏的小鼠模型Enpp1小鼠中研究了INZ - 701的药代动力学和药效学特征以及治疗效果。与野生型（WT）小鼠相比，Enpp1小鼠的血浆PPi检测不到，血浆磷酸盐水平较低，成纤维细胞生长因子23（FGF23）水平较高。食用含高磷和低镁的加速饮食的Enpp1小鼠会迅速出现临床症状，包括脱水、被毛粗糙、耳朵耷拉、腿部僵硬和弓背。用赋形剂处理的Enpp1小鼠具有上述临床症状，以及多个组织中的严重异位钙化和骨骼缺陷，这是在GACI和ARHR2患者中观察到的临床表型特征。我们的结果显示，单次注射INZ - 701后，PPi反应可持续超过3天。每隔一天用INZ - 701治疗ENPP1缺乏的小鼠8周，可恢复PPi的循环水平，防止所有测试器官发生病理性钙化，恢复生长参数，纠正骨骼缺陷，改善临床症状，并降低Enpp1小鼠的死亡率，证明了INZ - 701治疗ENPP1缺乏的潜力。© 2021美国骨与矿物质研究学会（ASBMR）
