Therapy for ectopic calcification in pseudoxanthoma elasticum

弹力纤维假黄瘤异位钙化的治疗

基本信息

批准号：
10763057
负责人：
JAMES W LARRICK
金额：
$ 28.58万
依托单位：
LARIX BIOSCIENCE, LLC
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：
2023-09-21 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10763057
关键词：
Adenosine Monophosphate Adult Age Animal Model Arterial calcification due to deficiency of CD73 Attenuated Blindness Calcium Cardiac Cardiovascular system Carrier Proteins Chronic Circulation Clinical Consensus Crystallization Diphosphates Disease Dose Drug Kinetics Effectiveness Enzymes Event Eye General Population Genes Goals Half-Life Hour Human Hungary Hydroxyapatites Individual Intermittent Claudication Ischemia Ischemic Stroke Knockout Mice Lead Liver Measures Mendelian disorder Modeling Molecular Weight Mus Netherlands Normal Range Oral Oral Administration Outcome Patients Peripheral Vascular Diseases Phase Physiology Plasma Pseudoxanthoma Elasticum Quality of life Replacement Therapy Risk Salts Series Skin Sodium Sodium Chloride Solubility Stomach Stroke Testing Therapeutic Time Tissues Toxic effect Toxicology Water Work absorption arterial calcification of infancy autosome calcification cerebrovascular effective therapy falls high risk inhibitor innovation inorganic phosphate lipophilicity loss of function mutation novel patient population plasma cell membrane glycoprotein PC-1 soft tissue stroke risk

项目摘要

Therapy for ectopic calcification in pseudoxanthoma elasticum Abstract Pseudoxanthoma elasticum (PXE) is a rare monogenic disease that leads to ectopic calcification of the eyes, skin, and vasculature. PXE results from loss-of-function mutations in the ABCC6 gene. Normally, ABCC6 transports ATP from the liver into circulation where it is then converted into adenosine monophosphate (AMP) and inorganic pyrophosphate (PPi) by the enzyme Ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1). PPi in circulation is a potent inhibitor of ectopic calcification; it antagonizes the ability of inorganic phosphate to crystallize with calcium to form hydroxyapatite. Patients with PXE have a 70% reduction of normal circulating levels of PPi which results in late-onset generalized systemic calcification. PPi replacement therapy has been challenging given the short half-life and misconceived notion that it could not be delivered orally. Recently, we have developed a proprietary gastric-release salt form of PPi for oral administration that achieves clinically meaningful increases in circulating PPi in mice and in humans. Orally delivered PPi in ABCC6-/- mice attenuates calcification and establishes proof-of-concept. In this Phase 1 project, we will conduct pharmacokinetic and toxicology studies and then evaluate Lys-PPi in an animal model of PXE. Phase 2 work will comprise IND-enabling studies, culminating in the filing of an IND. A successful outcome of this work will provide a proprietary mechanism-based first-in-class therapy for PXE and other disorders of abnormal ectopic calcification.

弹力纤维假黄瘤异位钙化的治疗抽象的弹性假黄瘤 (PXE) 是一种罕见的单基因疾病，会导致眼睛异位钙化，皮肤和脉管系统。 PXE 是由 ABCC6 基因功能丧失突变引起的。通常情况下，ABCC6 将 ATP 从肝脏输送到循环系统中，然后转化为单磷酸腺苷 (AMP) 外核苷酸焦磷酸酶/磷酸二酯酶-1 产生的无机焦磷酸盐 (PPi) （ENPP1）。循环中的 PPi 是异位钙化的有效抑制剂；它对抗无机物的能力磷酸盐与钙结晶形成羟基磷灰石。 PXE 患者的正常水平下降 70% PPi 的循环水平导致迟发性全身性钙化。 PPi替代疗法鉴于半衰期短以及不能口服的误解，该药物一直具有挑战性。最近，我们开发了一种用于口服给药的专有胃释放盐形式的 PPi，可实现小鼠和人类循环 PPi 的增加具有临床意义。 ABCC6-/- 小鼠口服 PPi 减轻钙化并建立概念验证。在这个第一阶段项目中，我们将进行药代动力学和毒理学研究，然后在 PXE 动物模型中评估 Lys-PPi。第二阶段工作将包括支持 IND 的研究，最终提交 IND。这项工作的圆满成功将为 PXE 和其他异常异位性疾病提供基于专有机制的一流疗法钙化。