Rescue of Lesch-Nyhan Disease

Lesch-Nyhan 病的拯救

基本信息

批准号：
10653714
负责人：
HYDER A JINNAH
金额：
$ 43.03万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653714
关键词：
Address Age Animal Model Autopsy Behavior Biological Brain Brain Diseases Cell Line Cell model Cerebral Palsy Characteristics Clinical Clinical Trials Defect Development Disease Embryonic Development Environment Enzymes Event Evolution Experimental Models Functional disorder Gene Expression Gout HPRT1 gene Hereditary Disease Human Hypoxanthine Phosphoribosyltransferase Impulsivity In Vitro Intellectual functioning disability Intervention Intervention Trial Kidney Calculi Knockout Mice Lead Lesch-Nyhan Syndrome Mental Retardation Metabolic Midbrain structure Modeling Molecular Molecular Abnormality Molecular Profiling Morphology Mutation Neurites Neurodevelopmental Disorder Neuronal Dysfunction Neurons Pathogenesis Pathologic Pathway interactions Patients Phenotype Poverty Pre-Clinical Model Process Production Purines Sampling Self-Injurious Behavior Source Specimen Stains Therapeutic Therapeutic Effect Therapeutic Intervention Translating Tyrosine 3-Monooxygenase Uncertainty Uric Acid clinical phenotype clinical translation conditional knockout dopaminergic neuron genetic variant in vitro Model in vivo induced pluripotent stem cell laser capture microdissection male mature animal motor impairment mouse model neurobehavioral neuron development new therapeutic target novel pre-clinical preclinical study prevent restoration stem cell model tool transcriptome sequencing

项目摘要

PROJECT SUMMARY Lesch-Nyhan disease (LND) is a neurodevelopmental disorder with a characteristic clinical phenotype that includes motor impairment resembling cerebral palsy, intellectual disability (mental retardation), difficult behaviors (severe self-injury and impulsivity), and overproduction of uric acid (leading to kidney stones and gout). LND is caused by pathological genetic variants in the HPRT1 gene, which encodes the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt). Over the past 20 years, great progress has been made in understanding the pathogenesis of the disease using cell models, animal models, and studies of human patients. These studies have indicated that the neurobehavioral abnormalities result in large part from dysfunction of midbrain dopamine neurons. These neurons do not die or show degenerative changes; they develop abnormally. The many preclinical advances have not been translated into clinical trials for LND for one major reason. This reason is that there is insufficient information regarding the developmental age at which interventions, such as restoration of HGprt, must be made. It is possible that intervention at any age could have a therapeutic effect by reversing functional metabolic defects responsible for arrested development or neuronal dysfunction. Alternatively, if HGprt deficiency causes irreversible defects during early development, then the intervention may have to occur at an early age to have any therapeutic value. The current proposal addresses this crucial question regarding the developmental window for intervention and rescue. We plan a three-tiered approach involving a novel cell model based on induced pluripotent stem cells (iPSCs), a novel Hprt1 conditional knockout mouse, and a unique bank of human LND brains collected at autopsy. The results will provide answers that address a major roadblock in translational efforts to rescue the phenotype of LND.

项目摘要 Lesch-nyhan病（LND）是一种神经发育疾病，具有特征性的临床表型包括运动障碍，类似于脑瘫，智力障碍（智力低下），困难行为（严重的自我伤害和冲动），以及尿酸的过量生产（导致肾结石和痛风）。 LND是由HPRT1基因中的病理性遗传变异引起的，该变异编码了嘌呤打捞酶低黄嘌呤 - 黄甘氨氨酸磷酸蛋白基转移酶（HGPRT）。在过去的20年中，取得了巨大进展使用细胞模型，动物模型和人类研究来理解疾病的发病机理患者。这些研究表明，神经行为异常大部分来自中脑多巴胺神经元功能障碍。这些神经元不会死亡或显示退化性变化。他们异常发展。许多临床前的进步尚未转化为LND的临床试验主要原因。这个原因是关于发育年龄的信息不足必须进行干预，例如HGPRT的恢复。任何年龄的干预都可能通过逆转功能性代谢缺陷来导致逮捕发育或神经元的功能代谢缺陷的治疗作用功能障碍。另外，如果HGPRT缺乏在早期发展过程中导致不可逆的缺陷，则干预可能必须在很小的时候就具有任何治疗价值。当前的提案地址这个关于干预和救援发展窗口的关键问题。我们计划三层涉及基于诱导多能干细胞（IPSC）的新细胞模型的方法，这是一种新型HPRT1条件淘汰鼠标，以及在尸检时收集的独特人类LND大脑。结果将提供答案这涉及转化努力以挽救LND表型的主要障碍。