Rescue of Lesch-Nyhan Disease

项目摘要 莱-尼二氏病（LND）是一种神经发育障碍，具有特征性临床表型， 包括类似脑瘫的运动障碍、智力残疾（精神发育迟滞）、 行为（严重的自我伤害和冲动），以及尿酸过度产生（导致肾结石和痛风）。 LND是由HPRT 1基因的病理性遗传变异引起的，HPRT 1基因编码嘌呤补救酶 次黄嘌呤-鸟嘌呤磷酸核糖基转移酶（HGprt）。在过去的20年里， 利用细胞模型、动物模型和人类研究， 患者这些研究表明，神经行为异常在很大程度上是由 中脑多巴胺神经元功能障碍。这些神经元不会死亡或出现退行性变化，它们 发育异常。许多临床前进展尚未转化为LND的临床试验， 主要原因。这是因为没有足够的信息，关于发育年龄， 必须进行干预，例如恢复HGPRT。任何年龄的干预都有可能 通过逆转导致发育停滞或神经元发育障碍的功能性代谢缺陷而产生的治疗效果。 功能障碍或者，如果HGprt缺陷在早期发育期间引起不可逆的缺陷，则 干预可能必须在早期进行才能具有治疗价值。目前的提案涉及 这是一个关于干预和救援的发展窗口的关键问题。我们计划一个三层的 一种涉及基于诱导多能干细胞（iPSC）的新型细胞模型的方法， 敲除小鼠和尸检时收集的人类LND大脑的独特库。结果将提供答案 这解决了翻译努力拯救LND表型的主要障碍。

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.