# Rescue of Lesch-Nyhan Disease

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $450,074

## Abstract

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.

## Key facts

- **NIH application ID:** 10298402
- **Project number:** 1R01NS119758-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** HYDER A JINNAH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $450,074
- **Award type:** 1
- **Project period:** 2021-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10298402

## Citation

> US National Institutes of Health, RePORTER application 10298402, Rescue of Lesch-Nyhan Disease (1R01NS119758-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10298402. Licensed CC0.

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