Novel Treatments for PXE

PXE 的新颖治疗方法

• 批准号: 10410523
• 负责人: Qiaoli Li
• 金额: $ 33.72万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-07 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410523
• 关键词: ATP Hydrolysis; Academy; Administrator; Affect; Alkaline Phosphatase; Arteries; Articular ligaments; Biological Assay; Biological Models; Biology; Blindness; Blood Circulation; Blood Vessels; Cardiovascular system; Centers of Research Excellence; Characteristics; Child; Clinical; Collaborations; Consultations; Cutaneous; Data; Dermatology; Development; Diagnosis; Diphosphates; Disease; Drug Kinetics; Elderly; Enzymes; Erythrocytes; Evaluation; Eye; Eye Development; Funding; Gastrointestinal Hemorrhage; Genes; Genetic; Genetic Models; Grant; Hepatocyte; Heritability; Human; Human Volunteers; Hypertension; Individual; Intermittent Claudication; Laboratories; Lead; Life; Liver; Lower Extremity; Mediating; Modeling; Morbidity - disease rate; Mus; Mutation; Myocardial Infarction; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Oral; Oral Administration; Pathogenicity; Pathologist; Patients; Peripheral; Pharmacological Treatment; Pharmacology; Phase I Clinical Trials; Phenotype; Plasma; Plasma Enhancement; Policies; Prenatal Diagnosis; Principal Investigator; Process; Program Research Project Grants; Progressive Disease; Pseudoxanthoma Elasticum; Rattus; Retina; Rodent; Rodent Model; Science; Scientist; Severities; Skin; Solid; Stroke; Testing; The Jackson Laboratory; Tissues; United States; United States National Institutes of Health; Universities; Vascular calcification; Visual Acuity; absorption; arterial calcification of infancy; base; calcification; clinical care; effective therapy; high risk; in vivo; in vivo Model; inhibitor; international center; mineralization; novel; pre-clinical; premature; programs; prototype; restoration; small molecule inhibitor; translational applications; ultrasound

ABSTRACT This application focuses on pseudoxanthoma elasticum (PXE), a prototype of heritable ectopic mineralization disorders. PXE is caused by mutations in the ABCC6 gene which encodes ABCC6, an efflux transporter expressed primarily in the liver. Characteristic clinical manifestations include cutaneous findings which signify the potential for development of ocular complications leading to loss of visual acuity and blindness, as well as cardiovascular involvement, including nephrogenic hypertension, intermittent claudication, bleeding from gastrointestinal arteries, early myocardial infarct and stroke. There is no specific or effective treatment for PXE or related ectopic mineralization disorders. Significant recent progress has been made in understanding the pathomechanistic details resulting in ectopic mineralization in PXE, and this information has now provided a platform to develop novel treatments. A particularly intriguing recent observation made by us is that release of ATP from hepatocytes to the circulation is dependent on functional ABCC6, and in the absence of ABCC6 activity, as in PXE, the plasma PPi levels are markedly reduced. Since PPi is a powerful anti-mineralization factor, reduced plasma PPi levels and particularly reduced PPi/Pi ratio allow ectopic mineralization in the peripheral tissues to ensue. In this study, we will test the unifying hypothesis that restoration of plasma PPi levels in patients with PXE will counteract the clinical manifestations of this devastating disease. To enhance plasma PPi levels, we have developed three Specific Aims proposing (a) pharmacologically enhanced release of cellular ATP either in an ABCC6-dependent or ABCC6-independent manner; (b) inhibition of tissue non- specific alkaline phosphatase (TNAP), the enzyme responsible for degradation of plasma PPi to Pi; and (c) oral administration of PPi with subsequent increases in plasma PPi levels. These plans are based on solid preliminary data, and they take advantage of well-characterized mouse and rat models developed and characterized in our laboratory, recapitulating clinical, histopathologic, ultrastructural and genetic features of PXE. Our plans also include a Phase I Clinical Trial to demonstrate the absorption of orally administered PPi in human volunteers and in patients with PXE with assay of pharmacokinetics in plasma. Collectively, our state-of-the-art studies utilizing in vivo model systems for PXE are expected to provide critical preclinical information of potential efficacy to restore plasma PPi levels in PXE, with subsequent inhibition of ectopic mineralization. Such information is reasonably expected to be useful towards development of pharmacologic treatments for PXE, as well as for other ectopic mineralization disorders, for which no effective or specific therapy is currently available.

摘要 本申请的重点是弹性假黄瘤（PXE），遗传性异位矿化的原型 紊乱PXE是由编码外排转运蛋白ABCC 6的ABCC 6基因突变引起的 主要在肝脏中表达。特征性临床表现包括皮肤发现， 可能发生导致视力丧失和失明的眼部并发症，以及 心血管受累，包括肾源性高血压、间歇性跛行、 胃肠道动脉，早期心肌梗死和中风。对于PXE没有特异性或有效的治疗方法 或相关的异位矿化障碍。最近在了解 病理机制的细节，导致异位矿化的PXE，这一信息现在已经提供了一个 开发新疗法的平台。我们最近观察到一个特别有趣的现象， 从肝细胞到循环的ATP依赖于功能性ABCC 6，并且在缺乏ABCC 6的情况下， 活动，如在PXE中，血浆PPi水平显著降低。由于PPi是一种强大的抗矿化剂， 降低的血浆PPi水平，特别是降低的PPi/Pi比值，使异位矿化在 周边组织也随之发生。在这项研究中，我们将测试统一的假设，即恢复血浆PPi PXE患者的血液中的高水平将抵消这种毁灭性疾病的临床表现。加强 血浆PPi水平，我们已经开发了三个具体目标，提出（a）PPi增强释放 （B）以ABCC 6依赖性或ABCC 6非依赖性方式抑制细胞ATP; 特异性碱性磷酸酶（TNAP），负责血浆PPi降解为Pi的酶;和（c）口服 PPi给药后血浆PPi水平升高。这些计划是基于坚实的 初步数据，他们利用良好的特点，小鼠和大鼠模型的发展， 在我们的实验室表征，概括了临床，组织病理学，超微结构和遗传特征， PXE。我们的计划还包括一项I期临床试验，以证明口服PPi的吸收， 人志愿者和患有PXE的患者中的血浆药代动力学测定。 总的来说，我们利用体内模型系统进行PXE的最新研究有望提供 在PXE中恢复血浆PPi水平的潜在有效性的关键临床前信息，随后 抑制异位矿化。有理由预期这些资料对发展有用 PXE的药物治疗，以及其他异位矿化疾病，没有 目前已有有效或特异性的治疗方法。

项目成果

Oral supplementation of inorganic pyrophosphate in pseudoxanthoma elasticum.

• DOI: 10.1111/exd.14498
• 发表时间: 2022-04
• 期刊: Experimental dermatology
• 影响因子: 3.6
• 作者: Kozák E;Fülöp K;Tőkési N;Rao N;Li Q;Terry SF;Uitto J;Zhang X;Becker C;Váradi A;Pomozi V
• 通讯作者: Pomozi V

GGCX mutations in a patient with overlapping pseudoxanthoma elasticum/cutis laxa-like phenotype.

• DOI: 10.1111/bjd.19576
• 发表时间: 2021-06
• 期刊: The British journal of dermatology
• 作者: Li D;Ryu E;Saeidian AH;Youssefian L;Oliphant E;Terry SF;Tong PL;Uitto J;Haass NK;Li Q
• 通讯作者: Li Q

Plasma Inorganic Pyrophosphate Deficiency Links Multiparity to Cardiovascular Disease Risk.

• DOI: 10.3389/fcell.2020.573727
• 发表时间: 2020
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Veiga-Lopez A;Sethuraman V;Navasiolava N;Makela B;Olomu I;Long R;van de Wetering K;Martin L;Aranyi T;Szeri F
• 通讯作者: Szeri F

Inorganic pyrophosphate is reduced in patients with systemic sclerosis.

• DOI: 10.1093/rheumatology/keab508
• 发表时间: 2022-03-02
• 期刊: RHEUMATOLOGY
• 影响因子: 5.5
• 作者: Hsu, Vivien M.;Kozak, Eszter;Li, Qiaoli;Bocskai, Marta;Schlesinger, Naomi;Rosenthal, Ann;McClure, Scott T.;Kovacs, Laszlo;Laszlo, Balint Balint;Szamosi, Szilvia;Szucs, Gabriella;Carns, Mary;Aren, Kathleen;Goldberg, Isaac;Varadi, Andras;Varga, John
• 通讯作者: Varga, John

The pathogenic c.1171A>G (p.Arg391Gly) and c.2359G>A (p.Val787Ile) ABCC6 variants display incomplete penetrance causing pseudoxanthoma elasticum in a subset of individuals.

• DOI: 10.1002/humu.24498
• 发表时间: 2022-12
• 期刊: HUMAN MUTATION
• 影响因子: 3.9
• 作者: Szeri, Flora;Miko, Agnes;Navasiolava, Nastassia;Kaposi, Ambrus;Verschuere, Shana;Molnar, Beatrix;Li, Qiaoli;Terry, Sharon F.;Boraldi, Federica;Uitto, Jouni;van de Wetering, Koen;Martin, Ludovic;Quaglino, Daniela;Vanakker, Olivier M.;Tory, Kalman;Aranyi, Tamas
• 通讯作者: Aranyi, Tamas