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Characterization of ENTPD1 as a drug target in PXE

ENTPD1 作为 PXE 药物靶标的表征

基本信息

批准号：
10790152
负责人：
Koen van de Wetering
金额：
$ 37.75万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-20 至 2025-09-19
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10790152
关键词：
ATP-Binding Cassette Transporters Affect Alleles Animal Model Arteries Binding Biological Availability Biological Models Blindness Blood Circulation Blood Vessels Cardiovascular system Cells Characteristics Chronic Kidney Failure Circulation Clinical Complex Connective and Soft Tissue Cutaneous Data Deposition Development Diabetes Mellitus Diagnosis Diphosphates Disadvantaged Disease Disease Progression Dose Drug Targeting Environment Extracellular Space Extrahepatic Eye Eye Development Factor V Family Functional disorder Gastrointestinal Hemorrhage Generations Genes Genetic Goals Half-Life Hepatic Hepatic Tissue Hepatocyte Heritability Homeostasis Human Hypertension In Vitro Individual Inherited Injections Intermittent Claudication Liver Mediating Metabolism Morbidity - disease rate Mus Mutation Myocardial Infarction Nucleotides Oral Administration Patients Pharmacological Treatment Plasma Production Progressive Disease Proteins Pseudoxanthoma Elasticum Regimen Replacement Therapy Research Residual state Retina Role Skin Solid Stroke Supplementation Testing Therapeutic Transgenic Organisms Visual Acuity calcification calcium phosphate ecto-nucleotidase effective therapy extracellular high risk in vivo in vivo Model inhibitor inorganic phosphate member mineralization mouse model novel therapeutic intervention pharmacologic plasma cell membrane glycoprotein PC-1 pre-clinical prevent prototype tripolyphosphate

项目摘要

This research will focus on pseudoxanthoma elasticum (PXE), the prototype of heritable ectopic mineralization disorders. Aberrant calcium phosphate deposition in PXE results in characteristic 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 effective treatment for PXE and the disease therefore progresses after diagnosis. PXE is caused by mutations in the ABCC6 gene which encodes ABCC6, an efflux transporter expressed primarily in the liver. Our group elucidated the pathophysiology underlying PXE, by showing that ABCC6 in hepatocytes mediates release of ATP into the blood circulation. Released ATP is extracellularly converted by the ecto-nucleotidase ENPP1 into 1 molecule of AMP and 1 molecule of the potent mineralization inhibitor inorganic pyrophosphate (PPi). PXE patients bearing defective ABCC6 have low PPi plasma concentrations, explaining their progressive calcification of soft connective tissues. Plasma PPi homeostasis is maintained through a complex network of proteins involved in ATP release, and ecto-nucleotidases metabolizing the released nucleotides. ENPP1 is crucial in this respect, as its activity underlies all PPi present in plasma. The ~40% of residual PPi present in plasma of PXE patients is formed out of ATP released by cells independent of ABCC6. Extracellular ATP is also subject to metabolism by other ecto- nucleotidases and the most important competitor of ENPP1 in the circulation is ENTPD1, which converts ATP into 1 molecule of AMP and 2 molecules of inorganic phosphate. Importantly, ENPP1 and ENTPD1 have opposing effects on extracellular PPi homeostasis and, consequently, ectopic calcification. In this study we propose to test the hypothesis that inhibition of ENTPD1 enhances extracellular PPi formation and prevents ectopic calcification in PXE patients We have developed two Specific Aims to test our hypothesis: (1) Thoroughly characterize how competition between ENPP1 and ENTPD1 affects extracellular PPi homeostasis in vitro and (2) Determine the effect of ENTPD1 on plasma PPi concentrations and ectopic calcification in Abcc6-/- mice in vivo. These plans are based on solid preliminary data, and they take advantage of a well-characterized mouse model developed and characterized in our department – the Abcc6-/- mouse –, which recapitulates the clinical, histopathologic, ultrastructural and genetic features of PXE in humans. Collectively, our state-of-the-art studies utilizing both in vitro and in vivo model systems are expected to provide critical preclinical information of the therapeutic potential of ENTPD1 inhibition to restore plasma PPi levels in PXE, with subsequent inhibition of ectopic calcification. Our findings are expected to not only inform development of pharmacologic treatments for PXE, but also for other ectopic calcification disorders, for which no effective or specific therapy is currently available.

本文将重点研究弹性假黄色瘤（PXE），它是遗传性异位矿化的原型