# Leveraging a newly identified EZH1 associated syndrome to explore pharmacological recovery of neurodevelopmental disorders

> **NIH NIH R21** · CHILDREN'S HOSP OF PHILADELPHIA · 2022 · $286,072

## Abstract

PROJECT SUMMARY/ABSTRACT
Neurodevelopmental disorders (NDDs) are a group of conditions that affect brain development and function often
leading to lifelong impairments in motor, language, cognitive and/or social behaviors. Increasing evidence involve
chromatin regulation in the pathogenic mechanism of neurodevelopmental disorders (NDDs), such as autism
and intellectual disabilities. Importantly, chromatin regulators constitute an attractive group for pharmacological
intervention given that most harbor enzymatic activities or well-defined binding domains that can be targeted.
The overarching goal of this proposal is to identify and test the therapeutic potential of a novel class of chromatin
regulator compounds. In particular our work will be focused on a NDD caused by EZH1 gain of function (GOF)
mutations that we have recently identified. EZH1, and its paralogue EZH2, catalyze histone H3 Lysine 27
methylation, a chromatin modification that marks and maintains transcriptional repression. Based on our
preliminary data we propose the hypothesis that the NDD in these patients is caused by dysregulation of H3K27
methylation leading to abnormal transcriptional repression of neuronal differentiation genes. Thus, we envision
a unique opportunity for pharmacological treatment of this patients using EZH inhibitors. To test this hypothesis,
we will dissect cellular and molecular mechanisms affected by EZH1 GOF mutations during neuronal
differentiation (Aim 1) and identify EZH1 inhibitors with potential to restore neurodevelopmental defects caused
by EZH1 GOF mutations (Aim 2). Results obtained here will serve as a proof of principle for the use of EZH
inhibitors to treat NDDs caused by EZH1 GOF mutations and potentially extend their application to other
NDDs with altered EZH1/2 and H3K27me3 mediated transcriptional repression.

## Key facts

- **NIH application ID:** 10528056
- **Project number:** 1R21HD107592-01A1
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Naiara Akizu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $286,072
- **Award type:** 1
- **Project period:** 2022-08-17 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10528056

## Citation

> US National Institutes of Health, RePORTER application 10528056, Leveraging a newly identified EZH1 associated syndrome to explore pharmacological recovery of neurodevelopmental disorders (1R21HD107592-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10528056. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*