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:
- 金额:$ 28.58万
- 依托单位:
- 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:
- 关键词:Adenosine MonophosphateAdultAgeAnimal ModelArterial calcification due to deficiency of CD73AttenuatedBlindnessCalciumCardiacCardiovascular systemCarrier ProteinsChronicCirculationClinicalConsensusCrystallizationDiphosphatesDiseaseDoseDrug KineticsEffectivenessEnzymesEventEyeGeneral PopulationGenesGoalsHalf-LifeHourHumanHungaryHydroxyapatitesIndividualIntermittent ClaudicationIschemiaIschemic StrokeKnockout MiceLeadLiverMeasuresMendelian disorderModelingMolecular WeightMusNetherlandsNormal RangeOralOral AdministrationOutcomePatientsPeripheral Vascular DiseasesPhasePhysiologyPlasmaPseudoxanthoma ElasticumQuality of lifeReplacement TherapyRiskSaltsSeriesSkinSodiumSodium ChlorideSolubilityStomachStrokeTestingTherapeuticTimeTissuesToxic effectToxicologyWaterWorkabsorptionarterial calcification of infancyautosomecalcificationcerebrovasculareffective therapyfallshigh riskinhibitorinnovationinorganic phosphatelipophilicityloss of function mutationnovelpatient populationplasma cell membrane glycoprotein PC-1soft tissuestroke 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.
弹性假性黄瘤异位钙化的治疗
摘要
弹性假黄瘤(PXE)是一种罕见的单基因疾病,导致眼睛的异位钙化,
皮肤和血管系统。PXE是由ABCC6基因功能丧失突变引起的。正常情况下,ABCC6
将三磷酸腺苷从肝脏输送到循环中,然后在循环中转化为一磷酸腺苷(AMP)
和无机焦磷酸(PPI),由胞外核苷酸焦磷酸酶/磷酸二酯酶-1酶催化
(ENPP1)。循环中的PPI是一种有效的异位钙化抑制剂;它拮抗无机钙的能力
磷酸盐与钙结晶形成羟基磷灰石。PXE患者的正常值降低了70%
循环中的PPI水平会导致迟发性全身钙化。PPI替代疗法
考虑到它的半衰期很短,而且人们错误地认为它不能口头传递,这一点一直具有挑战性。
最近,我们开发了一种专有的胃释盐形式的PPI口服给药,实现了
在小鼠和人类中循环PPI的临床意义增加。口服PPI对ABCC6-/-小鼠的影响
减少钙化,并建立概念验证。在这个第一阶段的项目中,我们将进行
在PXE动物模型上进行药代动力学和毒理学研究,然后评估Lys-PPI。第2阶段工作
将包括支持IND的研究,最终提交IND。这项工作的成功成果将是
为PXE和其他异常异位障碍提供基于专利机制的一流治疗
钙化。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JAMES W LARRICK其他文献
JAMES W LARRICK的其他文献
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