# Modeling Inherited Neurodevelopmental Disorders with Human Induced Pluripotent Stem Cells

> **NIH NIH R01** · EMORY UNIVERSITY · 2022 · $586,470

## Abstract

PROJECT SUMMARY
The pathogenesis of neurodevelopmental disorders is challenging to address for many reasons. The human
brain is relatively inaccessible for direct evaluation, human autopsy and imaging studies provide limited
opportunities to study molecular or cellular mechanisms, animal models sometimes do not replicate important
disease features, and immortalized neuron-like cell lines cannot be used to model normal development. Induced
pluripotent stem cells (iPSCs) provide a powerful new experimental tool to address these limitations. They can
be created from patients with known developmental disorders caused by defined mutations, they provide a
renewable resource, and they can be differentiated into specific cell lineages to provide species-specific and
lineage-specific experimental models to study developmental mechanisms at the cellular and molecular levels.
In the current proposal we address several fundamental questions that are broadly relevant to iPSC modeling
for neurodevelopmental disorders. We focus on Lesch-Nyhan disease (LND) as a prototype disorder, because
it has numerous features that make it an unusually tractable Mendelian disorder for iPSC modeling. LND and
its milder variants are caused by mutations in the HPRT1 gene, resulting in deficiency of the purine salvage
enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt). The neurobehavioral abnormalities in this
disorder have been linked with developmental dysfunction of brain dopamine neurons. Aim 1 focuses on
establishing a well-characterized bank of iPSCs across the spectrum of disease severity, to address issues
related to how specific mutations causing different disease severity are reflected in iPSC models. Aim 2 focuses
on establishing a well-characterized bank of isogenic iPSCs in which specific mutations have been introduced
via gene editing methods, to address issues related to the genetic background of individuals from which iPSC
models are derived. In Aim 3 we differentiate these lines into dopamine neurons, to address how iPSC models
can reveal the timing and mechanisms of pathogenesis related to LND. Overall, this project will address
fundamental questions that are broadly relevant for iPSC modeling of neurodevelopmental disorders, as well as
more specific insights into the pathogenesis of the neurobehavioral abnormalities of LND.

## Key facts

- **NIH application ID:** 10397399
- **Project number:** 5R01NS109242-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** HYDER A JINNAH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $586,470
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10397399

## Citation

> US National Institutes of Health, RePORTER application 10397399, Modeling Inherited Neurodevelopmental Disorders with Human Induced Pluripotent Stem Cells (5R01NS109242-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10397399. Licensed CC0.

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