ENZYME THERAPY FOR CKD-MBD: BREAKING THE BARRIER OF VASCULAR CALCIFICATION

CKD-MBD 酶疗法：打破血管钙化障碍

• 批准号: 9891444
• 负责人: DEMETRIOS BRADDOCK
• 金额: $ 23.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-20 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891444
• 关键词: Address; Adenine; Appearance; Area; Bioavailable; Biochemistry; Biological; Biological Products; Biomechanics; Blood Vessels; Bone Density; Bone Diseases; Calcium; Cardiovascular system; Chronic Kidney Failure; Data; Development; Dialysis procedure; Diet; Diphosphates; Disease; Drops; Electrons; End stage renal failure; Enzymes; Fc domain; Fracture; Genetic Models; Goals; Half-Life; Hemodialysis; Histology; Human; Hydroxyapatites; IgG1; Image; Investigational Therapies; Knowledge; Measures; Mechanics; Medial; Medical; Metabolism; Methods; Minerals; Modeling; Mus; Nephrectomy; Osteocytes; Osteogenesis; Osteomalacia; Osteopenia; Osteoporosis; Outcome; Pathogenesis; Patients; Pharmacodynamics; Phenotype; Physiologic calcification; Plasma; Play; Polysaccharides; Property; Protein Engineering; Rattus; Resistance; Risk; Rodent Model; Role; Syndrome; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Uremia; Vascular calcification; Weight; arterial calcification of infancy; base; bone; bone turnover; calcification; cortical bone; design; enzyme replacement therapy; enzyme therapy; fracture risk; hemodynamics; improved; in vivo; inhibitor/antagonist; innovation; long bone; microCT; mineralization; mortality; mortality risk; mouse model; novel; novel therapeutics; skeletal; soft tissue; therapeutic development

Abstract: The medial arterial calcifications (MAC) observed in chronic kidney disease (CKD) progress irreversibly despite current treatment, and contributes to the poor cardiovascular outcomes in these patients. In addition, the risk of bone fracture in CKD patients has remained unchanged for the last 20 years despite improvement in the fracture risk in other mineralization disorders. The lack of progress suggests that despite the significant medical need, current therapeutics treating the mineralization disorder present in CKD-MBD are ineffective. Pyrophosphate (PPi) is a direct inhibitor of hydroxyapatite formation, and patients on hemodialysis have reduced plasma PPi levels. The appearance and progression of MAC correlates inversely with plasma pyrophosphate (PPi) concentrations. In addition, patients with CKD also develop alterations in skeletal metabolism referred to as chronic kidney disease – bone and mineral disorder (CKD-MBD). Reduced bone mineral density is also present in rodent models of deficient ENPP1 and low plasma PPi, supporting the notion ENPP1/ PPi may play a role in the bone mineralization disorder present in CKD-MBD. A major experimental barrier to investigating the role of ENPP1/PPi in CKD is the lack of an ENPP1 enzyme replacement therapy (ERT) which normalizes plasma [PPi] in vivo. We have developed a soluble ENPP1 biologic agent overcoming these barriers and have established its efficacy in a lethal genetic model of vascular calcification, low plasma PPi, elevated FGF23, and progressive uremia called Generalized Arterial Calcification of Infancy (GACI). The objective of this proposal is to determine the role of ENPP1/PPi in the mineralization imbalances present in CKD-MBD. Our central hypothesis is that correcting low plasma [PPi] and ENPP1 deficiency with ENPP1 ERT will inhibit medial wall vascular calcifications, improve arterial hemodynamic properties, and improve the bone mineralization deficits present in CKD-MBD. Our hypothesis is based on our preliminary data showing that murine models of CKD-MBD drop plasma [PPi] by 50%, and that treating these mice with ENPP1 ERT significantly reduces ectopic calcifications and improves bone biomechanics in these models. Our hypothesis is also supported by our own preliminary data that Enpp1 deficiency increases cortical bone mineralization which damages the cortical bone osteocyte microenvironment and significantly decreases bone formation rates, resulting in marked osteopenia. We will validate our hypothesis by demonstrating the efficacy of ENPP1 ERT in murine models of CKD-MBD by documenting the effects of the therapeutic on the increased ectopic soft tissue calcifications and decreased bone mineralization present in these models.

摘要：在慢性肾脏疾病（CKD）中观察到的介导的伪影（MAC）进行了不可逆转的目前治疗，并导致这些患者的心血管结局不良。此外，在过去20年中，CKD患者骨折的风险一直保持不变。缺乏进展表明，需要大量医疗需求，当前治疗CKD-MBD中矿化障碍的治疗无效。焦磷酸盐（PPI）是羟磷灰石形成的直接抑制剂，血液透析患者的血浆PPI水平降低。 MAC的外观和进展与血浆焦磷酸（PPI）浓度成反比。此外，CKD患者还会发展出称为慢性肾脏疾病 - 骨骼和矿物质疾病（CKD-MBD）的骨骼代谢改变。在不足的ENPP1和低血浆PPI的啮齿动物模型中，骨矿物质密度也降低，支持概念ENPP1/ PPI可能在CKD-MBD中存在的骨矿化障碍中起作用。研究ENPP1/PPI在CKD中的作用的主要实验障碍是缺乏ENPP1酶替代疗法（ERT），该酶替代疗法（ERT）在体内将血浆[PPI]归一化。我们已经开发了一种克服这些障碍的可溶性ENPP1生物学剂，并在血管钙化的致命遗传模型，低血浆PPI，FGF23升高和渐进性尿症中确立了其有效性，称为概括性动脉钙化婴儿的婴儿（GACI）。该提案的目的是确定ENPP1/PPI在CKD-MBD中存在的矿化失衡中的作用。我们的中心假设是，用ENPP1 ERT纠正低血浆[PPI]和ENPP1缺乏症将抑制内侧壁血管钙化，改善动脉血液动力学特性并改善CKD-MBD中存在的骨矿化定义。我们的假设基于我们的初步数据，表明CKD-MBD降低血浆[PPI]的鼠模型减少了50％，并且用ENPP1 ERT处理这些小鼠可显着降低生态钙化并改善这些模型中的骨生物力学。我们的假设也得到了我们自己的初步数据的支持，即ENPP1缺乏增加皮质骨矿化，从而损害皮质骨骨细胞微环境并显着降低骨形成率，从而显着降低骨质骨质。我们将通过记录治疗方法对增加的生态软组织钙化的影响和改善这些模型中存在的骨矿化的影响，来证明在CKD-MBD的鼠模型中的有效性来验证我们的假设。