Pharmacologic Intervention for Ectopic Calcification

异位钙化的药物干预

• 批准号: 10359773
• 负责人: Qiaoli Li
• 金额: $ 17.35万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359773
• 关键词: Acetazolamide; Acidosis; Affect; Alkaline Phosphatase; Animal Model; Area; Biological; Calcium; Carbonic Anhydrase Inhibitors; Cardiovascular system; Centers of Research Excellence; Clinical; Clinical Management; Clinical Trials; Collaborations; Connective and Soft Tissue; Coronary artery; Data; Deposition; Development; Diagnosis; Diphosphates; Disease; Drug Kinetics; Durapatite; Excision; Eye; Fetal Development; Fetal Heart; Fetus; Future; Genes; Genetic; Genetic Diseases; Goals; Hereditary Disease; Heritability; Hydroxyapatites; Individual; Infant; International; Intervention; Investigation; Life; Minerals; Modeling; Morbidity - disease rate; Mothers; Mus; Mutation; Newborn Infant; Outcome; Pathologic; Patient advocacy; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phenotype; Physiological; Plasma; Pregnancy; Prenatal Diagnosis; Prevalence; Prevention; Pseudoxanthoma Elasticum; Rodent Model; Signal Transduction; Skin; Solubility; Testing; Therapeutic; Time; Tissues; Toxicology; United States Food and Drug Administration; Universities; Vascular calcification; Work; advocacy organizations; arterial calcification of infancy; base; calcification; clinical care; design; dietary; early onset; inhibitor; insight; international center; loss of function mutation; mineralization; mortality; mouse model; novel; novel strategies; novel therapeutics; offspring; osteogenic; postnatal; pre-clinical; preclinical development; pregnant; prenatal; prevent; prototype; soft tissue; therapeutic development; ultrasound

ABSTRACT This application revolves around ectopic calcification disorders, pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI), two autosomal recessive diseases with considerable morbidity and mortality due to calcium hydroxyapatite deposition in the skin, eyes, and the cardiovascular system. There is currently no effective or specific treatment for the ectopic calcification in these disorders. We have developed and characterized mouse models for both PXE and GACI, and these mice now form the platform for preclinical development of therapeutic strategies for these two, currently intractable conditions. The unifying pathological finding in these ectopic calcification disorders is reduced plasma inorganic pyrophosphate (PPi) levels. While significant insight was gained in these disorders, disease mechanism-directed treatment by targeting PPi deficiency prevented new calcification but failed to remove existing ectopic calcification. In this proposal, we will test the overall hypothesis that counteracting ectopic calcification, either by prevention of mineral deposition in the fetus and/or removal of the existing deposits postnatally, will provide treatment approaches with clinical stabilization or cure for patients with PXE or GACI. The therapeutic drug, acetazolamide, has the great potential of counteracting ectopic calcification, primarily due to its physicochemical and cellular mechanisms which are independent of plasma PPi levels. We will specifically focus on two areas of investigation: (a) Prevention of prenatal arterial calcification in GACI by administration of acetazolamide to the mothers during pregnancy, with or without continued treatment of the newborns; this drug will be repurposed from its previous applications to treat various calcification disorders; and (b) We will further focus our efforts to remove existing calcification in PXE and GACI by administration of acetazolamide. These studies will utilize combined prevention and removal approaches to counteract ectopic calcification, providing scientific premise to the investigation. Collectively, our proposed studies will provide critical translational information from preclinical approaches that will allow development of novel treatment for currently intractable disorders PXE and GACI. We also expect that our findings will advance clinical management of ectopic calcification in general, potentially applicable to a number of other diseases, both genetic and acquired.

摘要

项目成果

Genetic heterogeneity of heritable ectopic mineralization disorders in a large international cohort.

• DOI: 10.1016/j.gim.2021.08.011
• 发表时间: 2022-01
• 期刊: Genetics in medicine : official journal of the American College of Medical Genetics
• 作者: Saeidian AH;Youssefian L;Huang J;Touati A;Vahidnezhad H;Kowal L;Caffet M;Wurst T;Singh J;Snook AE;Ryu E;Fortina P;Terry SF;Schoenecker JG;Uitto J;Li Q
• 通讯作者: Li Q

ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification.

• DOI: 10.1371/journal.pgen.1010192
• 发表时间: 2022-04
• 期刊: PLoS genetics
• 影响因子: 4.5

Functional Assessment of Missense Variants in the ABCC6 Gene Implicated in Pseudoxanthoma Elasticum, a Heritable Ectopic Mineralization Disorder.

与弹性假黄瘤（一种遗传性异位矿化障碍）有关的 ABCC6 基因错义变异体的功能评估。

• DOI: 10.1016/j.jid.2021.08.435
• 发表时间: 2022-04
• 期刊: The Journal of investigative dermatology
• 作者: Kowal L;Huang J;Luo H;Singh J;Snook AE;Uitto J;Li Q
• 通讯作者: Li Q

Novel Treatments for PXE: Targeting the Systemic and Local Drivers of Ectopic Calcification.

• DOI: 10.3390/ijms242015041
• 发表时间: 2023-10-10
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

Mutation update: Variants of the ENPP1 gene in pathologic calcification, hypophosphatemic rickets, and cutaneous hypopigmentation with punctate keratoderma.

• DOI: 10.1002/humu.24391
• 发表时间: 2022-09
• 期刊: HUMAN MUTATION
• 影响因子: 3.9
• 作者: Ralph, Douglas;Levine, Michael A.;Richard, Gabriele;Morrow, Michelle M.;Flynn, Elizabeth K.;Uitto, Jouni;Li, Qiaoli
• 通讯作者: Li, Qiaoli