Towards Improved Therapy for Classic Galactosemia

改进经典半乳糖血症的治疗

• 批准号: 9560851
• 负责人: Kent Lai
• 金额: $ 31.64万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-08 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9560851
• 关键词: Address; Adult; Affect; Animal Model; Ataxia; Biological; Biological Markers; Cells; Cessation of life; Chemicals; Chronic; Classical galactosemia; Crystallography; Defect; Diet; Disease; Disease susceptibility; Dissociation; Dose; Drug Kinetics; Early Diagnosis; Early treatment; Effectiveness; Escherichia coli; Excretory function; Exposure to; Female; Galactose; Galactose Metabolism Pathway; Genes; Glycoproteins; Goals; Growth; Gut associated lymphoid tissue; Hemorrhage; Hepatotoxicity; Human; In Vitro; Inborn Errors of Metabolism; Inherited; Lead; Life; Lipids; Measures; Medical; Metabolic Pathway; Metabolism; Methods; Modality; Modification; Mus; Mutant Strains Mice; Neonatal; Neonatal Screening; Neurologic; Neuropsychology; Newborn Infant; Online Mendelian Inheritance In Man; Organ; Pathogenicity; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphatidylinositols; Play; Preclinical Testing; Production; Property; Proteins; Regimen; Role; Safety; Savings; Scientist; Sepsis; Signal Transduction; Solubility; Speech Delay; Structure; Syndrome; TNFSF5 gene; Testing; Therapeutic; Tissues; Translating; Translations; Treatment Efficacy; Tremor; United States; United States National Institutes of Health; absorption; acute toxicity; base; chemical synthesis; design; dietary restriction; efficacy study; experimental study; galactokinase; galactose-1-phosphate; glycosylation; high throughput screening; high throughput technology; improved; improved outcome; in vivo; inhibitor/antagonist; innovation; knockout gene; motor impairment; mouse model; mutant; nanomolar; novel; novel therapeutics; pharmacokinetic characteristic; prevent; primary ovarian insufficiency; process optimization; pup; screening program; sex; small molecule; small molecule inhibitor; subfertility

PROJECT SUMMARY / ABSTRACT Hereditary deficiency of galactose-1-phosphate uridylyltransferase (GALT, E.C. 2.7.7.12) activity in humans can lead to a potentially lethal disease called Classic Galactosemia (OMIM 230400). Despite the life-saving consequences of newborn screening, early diagnosis, and a galactose-restricted diet, many patients with Classic Galactosemia suffer later in life from complications including growth, neuropsychological, and speech delays as well as primary ovarian insufficiency (POI). There are currently no satisfactory treatments available to prevent/alleviate any of these complications. Several lines of evidence, which include the absence of acute toxicity syndrome and chronic complications in patients with inherited deficiency of galactokinase (GALK1), as well as the reversal of glycosylation/neurological defects in GALT-less fruitflies by deleting the dGALK gene, indicated that galactose-1 phosphate (gal-1P), product of GALK1 and an intermediate accumulated in GALT deficiency, is toxic in susceptible tissues and plays a pathogenic role in the organ- specific complications of Classic Galactosemia. Therefore, we hypothesize that pharmacological inhibition of human GALK1, which will prevent the accumulation of toxic gal-1P, can confer the less severe phenotype of GALK1 deficiency and improve the outcome of Classic Galactosemia. To test this hypothesis, we collaborated with scientists at NIH/NCATS/NCGC and launched a quantitative high-throughput screening (qHTS) campaign to identify small molecule inhibitors of human GALK1. After extensive characterization and optimization efforts of the positives, we have identified some unique and promising lead GALK1 inhibitors with dissociation constants (a measure of the strength of the inhibitors) at the nanomolar range, as well as favorable cell-based and in vivo activities. The translation of these promising small molecule GALK1 inhibitors into useful therapeutics, however, requires further chemical modifications and in vivo studies in a mammalian animal model. To prepare for the testing of the preclinical in vivo studies of selected GALK1 inhibitors, we have constructed a new GalT-gene trapped (GALT-deficient) mouse model. Expanded characterization of the new mouse model revealed disease-relevant phenotypes, which include galactose sensitivity in the newborn mutant pups, subfertility of the adult female mutants, motor impairment and growth restriction in mutant mice of both sexes. Specifically, in Aim 1 of this application, we propose to further optimize the selected GALK1 lead inhibitors to improve their biological activities and drug-like properties; and in Aim 2, we will evaluate the in vivo efficacy of the selected GALK1 inhibitors in ameliorating selected disease-relevant phenotypes in the homozygous GalT-gene trapped mice.

项目摘要/摘要 人类遗传性半乳糖-1-磷酸尿苷转移酶(GalT，E.C.2.7.7.12)活性缺陷可导致 一种潜在的致命疾病，称为典型的半乳糖血症(OMIM 230400)。尽管有拯救生命的后果， 新生儿筛查、早期诊断和限制半乳糖饮食，许多典型的半乳糖血症患者后来会受到影响 生活中的并发症，包括生长、神经心理和语言发育迟缓以及原发卵巢 功能不全(POI)。目前还没有令人满意的治疗方法来预防/缓解这些症状。 并发症。 几条证据，其中包括患者没有急性毒性综合征和慢性并发症 遗传性半乳糖激酶缺乏(GALK1)，以及糖基化/神经缺陷逆转 通过删除dGALK基因，表明GALK1和GALK1的产物半乳糖-1磷酸(GAL-1P) 谷丙转氨酶缺乏时积累的一种中间体，在敏感组织中有毒，并在器官中起致病作用- 典型半乳糖血症的特殊并发症。因此，我们假设药物对人类的抑制作用 GALK1可以防止毒性GAL-1P的积累，可以赋予较轻的GALK1缺乏症表型 改善典型半乳糖血症的转归。为了验证这一假设，我们与科学家们在 NIH/NCATS/NCGC，并发起了一项定量高通量筛选(QHTS)活动以识别小分子 人类GALK1的抑制剂。经过对积极因素的广泛表征和优化努力，我们已经确定 一些独特的和有希望的具有解离常数的铅GALK1抑制剂(衡量GALK1抑制剂的强度) 抑制剂)在纳摩尔范围内，以及良好的细胞和体内活性。这些词的翻译 然而，有希望将小分子GALK1抑制剂转化为有用的治疗药物，需要进一步的化学修饰 并在哺乳动物动物模型中进行活体研究。为临床前体内研究的测试做准备 GALK1抑制剂，我们构建了一种新的GALT基因捕获(GALT缺陷)小鼠模型。已扩展 对新的小鼠模型的表征揭示了与疾病相关的表型，其中包括对半乳糖的敏感性 新生的突变幼鼠，成年雌性突变小鼠的不育，突变小鼠的运动障碍和生长受限 两性都有。具体地说，在本申请的目标1中，我们建议进一步优化所选的GALK1先导抑制剂 以改善它们的生物活性和类药物特性；在目标2中，我们将评估 选择性GALK1抑制剂改善GALT纯合子捕获的疾病相关表型 老鼠。