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: 10348745
• 负责人: DEMETRIOS BRADDOCK
• 金额: $ 22.07万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10348745
• 关键词: Address; Adenine; Appearance; Area; 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; efficacy validation; enzyme replacement therapy; enzyme therapy; fracture risk; hemodynamics; improved; in vivo; inhibitor; 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：尽管目前的治疗，在慢性肾脏病（CKD）中观察到的中膜动脉钙化（MAC）仍不可逆地进展，并导致这些患者的心血管结局较差。此外，尽管其他矿化疾病的骨折风险有所改善，但CKD患者的骨折风险在过去20年中保持不变。缺乏进展表明，尽管有显著的医疗需求，但目前治疗CKD-MBD中存在的矿化障碍的疗法是无效的。 焦磷酸盐（PPi）是羟基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的出现和进展与血浆焦磷酸盐（PPi）浓度呈负相关。此外，CKD患者还发生骨骼代谢改变，称为慢性肾脏病-骨和矿物质障碍（CKD-MBD）。骨矿物质密度降低也存在于缺乏ENPP 1和低血浆PPi的啮齿动物模型中，支持ENPP 1/ PPi可能在CKD-MBD中存在的骨矿化障碍中发挥作用的观点。研究ENPP 1/PPi在CKD中的作用的主要实验障碍是缺乏使体内血浆[PPi]正常化的ENPP 1酶替代疗法（ERT）。我们已经开发了一种可溶性ENPP 1生物制剂，克服了这些障碍，并在血管钙化、低血浆PPi、升高的FGF 23和进行性尿毒症的致死性遗传模型（称为婴儿全身动脉钙化（GACI））中确立了其疗效。 本提案的目的是确定ENPP 1/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ENPP 1 ERT纠正低血浆[PPi]和ENPP 1缺乏将抑制中壁血管钙化，改善动脉血流动力学特性，并改善CKD-MBD中存在的骨矿化缺陷。我们的假设是基于我们的初步数据，显示CKD-MBD小鼠模型的血浆[PPi]下降了50%，并且用ENPP 1 ERT治疗这些小鼠显著减少了这些模型中的异位钙化并改善了骨生物力学。我们的假设也得到了我们自己的初步数据的支持，即Enpp 1缺乏会增加皮质骨矿化，这会破坏皮质骨骨细胞微环境，并显着降低骨形成率，导致明显的骨质减少。我们将通过证明ENPP 1 ERT在CKD-MBD小鼠模型中的疗效来验证我们的假设，方法是记录治疗剂对这些模型中异位软组织钙化增加和骨矿化减少的影响。

项目成果

Systematic characterization of enzyme activity on ENPP1 deficiency disease phenotype.

ENPP1 缺乏症表型酶活性的系统表征。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Ansh,AnenyaJ;Stabach,PaulR;Carpenter,ThomasO;Ferreira,CarlosR;Braddock,Demetrios
• 通讯作者: Braddock,Demetrios

Response of enthesopathy in ENPP1 deficiency to enzyme replacement therapy in murine models and enthesopathy comorbidities and quality of life in ENPP1-deficient adults.

ENPP1 缺陷的附着点病对小鼠模型中酶替代疗法的反应以及 ENPP1 缺陷成人的附着点病合并症和生活质量。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Ansh,AnenyaJ;Nester,Catherine;O'Brien,Christine;Stabach,PaulR;Murtada,Sae-Il;Lester,EthanR;Khursigara,Gus;Molloy,Liz;Carpenter,ThomasO;Ferreira,CarlosR;Braddock,DemetriosT
• 通讯作者: Braddock,DemetriosT

Characterization of hearing-impairment in Generalized Arterial Calcification of Infancy (GACI).

• DOI: 10.1186/s13023-022-02410-w
• 发表时间: 2022-07-19
• 期刊: ORPHANET JOURNAL OF RARE DISEASES
• 影响因子: 3.7
• 作者: Theng, Elizabeth H.;Brewer, Carmen C.;Oheim, Ralf;Zalewski, Christopher K.;King, Kelly A.;Delsmann, Maximillian M.;Rolvien, Tim;Gafni, Rachel, I;Braddock, Demetrios T.;Kim, H. Jeffrey;Ferreira, Carlos R.
• 通讯作者: Ferreira, Carlos R.