Rescue of Lesch-Nyhan Disease

Lesch-Nyhan 病的拯救

基本信息

批准号：
10298402
负责人：
HYDER A JINNAH
金额：
$ 45.01万
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/10298402
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 Purines Sampling Self-Injurious Behavior Source Specimen Stains Therapeutic Therapeutic Effect Therapeutic Intervention Translating Tyrosine 3-Monooxygenase Uncertainty Uric Acid base clinical phenotype clinical translation conditional knockout disorder control 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.

项目概要 Lesch-Nyhan 病 (LND) 是一种神经发育障碍，其临床表型特征为包括类似脑瘫的运动障碍、智力障碍（精神发育迟滞）、困难行为（严重自残和冲动）以及尿酸过多（导致肾结石和痛风）。 LND 是由 HPRT1 基因的病理性遗传变异引起的，该基因编码嘌呤补救酶次黄嘌呤鸟嘌呤磷酸核糖转移酶（HGprt）。过去20年，取得了巨大进步利用细胞模型、动物模型和人类研究来了解该疾病的发病机制患者。这些研究表明，神经行为异常很大程度上是由于中脑多巴胺神经元功能障碍。这些神经元不会死亡或表现出退行性变化；他们发育异常。许多临床前进展尚未转化为 LND 的临床试验之一主要原因。原因是关于发育年龄的信息不足。必须采取干预措施，例如恢复 HGprt。任何年龄的干预都有可能通过逆转导致发育或神经元停滞的功能代谢缺陷而产生治疗效果功能障碍。或者，如果 HGprt 缺乏在早期发育过程中导致不可逆转的缺陷，那么干预可能必须在早期进行才能具有治疗价值。当前提案地址这个关键问题涉及干预和救援的发展窗口。我们计划三层该方法涉及基于诱导多能干细胞 (iPSC) 的新型细胞模型，这是一种新型 Hprt1 条件条件细胞基因敲除小鼠，以及尸检时收集的独特的人类 LND 大脑库。结果将给出答案解决了拯救 LND 表型的转化努力中的一个主要障碍。