Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, Shinagawa-Ku, Tokyo, 140-8710, Japan.
Sci Rep. 2022 Nov 18;12(1):19852. doi: 10.1038/s41598-022-23892-5.
Pseudoxanthoma elasticum (PXE) is a multisystem, genetic, ectopic mineralization disorder with no effective treatment. Inhibition of tissue-nonspecific alkaline phosphatase (TNAP) may prevent ectopic soft tissue calcification by increasing endogenous pyrophosphate (PPi). This study evaluated the anticalcification effects of DS-1211, an orally administered, potent, and highly selective small molecule TNAP inhibitor, in mouse models of PXE. Calcium content in vibrissae was measured in KK/HlJ and ABCC6 mice after DS-1211 administration for 13-14 weeks. Pharmacokinetic and pharmacodynamic effects of DS-1211 were evaluated, including plasma alkaline phosphatase (ALP) activity and biomarker changes in PPi and pyridoxal-phosphate (PLP). Anticalcification effects of DS-1211 through TNAP inhibition were further evaluated in ABCC6 mice with genetically reduced TNAP activity, ABCC6/TNAP and ABCC6/TNAP. In KK/HlJ and ABCC6 mouse models, DS-1211 inhibited plasma ALP activity in a dose-dependent manner and prevented progression of ectopic calcification compared with vehicle-treated mice. Plasma PPi and PLP increased dose-dependently with DS-1211 in ABCC6 mice. Mice with ABCC6/TNAP phenotype had significantly less calcification and higher plasma PPi and PLP than ABCC6/TNAP mice. TNAP plays an active role in pathomechanistic pathways of dysregulated calcification, demonstrated by reduced ectopic calcification in mice with lower TNAP activity. DS-1211 may be a potential therapeutic drug for PXE.
弹性假黄瘤（PXE）是一种多系统遗传性异位矿化疾病，目前尚无有效治疗方法。组织非特异性碱性磷酸酶（TNAP）的抑制作用可能通过增加内源性焦磷酸（PPi）来预防异位软组织钙化。本研究评估了口服、强效、高度选择性小分子 TNAP 抑制剂 DS-1211 在 PXE 小鼠模型中的抗钙化作用。在给予 DS-1211 13-14 周后，测量 KK/HlJ 和 ABCC6 小鼠触须中的钙含量。评估了 DS-1211 的药代动力学和药效学作用，包括血浆碱性磷酸酶（ALP）活性以及 PPi 和吡哆醛-5-磷酸（PLP）的生物标志物变化。通过 TNAP 抑制评估了 DS-1211 在 TNAP 活性降低的 ABCC6 小鼠、ABCC6/TNAP 和 ABCC6/TNAP 中的抗钙化作用。在 KK/HlJ 和 ABCC6 小鼠模型中，DS-1211 呈剂量依赖性抑制血浆 ALP 活性，并与载体处理的小鼠相比，阻止了异位钙化的进展。ABCC6 小鼠中，DS-1211 可使血浆 PPi 和 PLP 呈剂量依赖性增加。与 ABCC6/TNAP 小鼠相比，ABCC6/TNAP 表型的小鼠钙化明显减少，血浆 PPi 和 PLP 升高。TNAP 在调节钙化失调的发病机制途径中发挥积极作用，这表现在 TNAP 活性降低的小鼠中异位钙化减少。DS-1211 可能是 PXE 的一种潜在治疗药物。
