Rescue of Lesch-Nyhan Disease

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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.