# Small Molecule Therapeutic Discovery for Angelman Syndrome

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $558,226

## Abstract

PROJECT SUMMARY
Angelman syndrome is a severe neurodevelopmental disorder caused by maternal allele deletions of UBE3A.
In neurons, the paternal allele of UBE3A is epigenetically silenced. Unsilencing the paternal allele of UBE3A
offers a potentially transformative opportunity for treating Angelman syndrome. We recently discovered a small
molecule that unsilences the paternal allele of UBE3A in neurons cultured from Angelman syndrome model
mice or from stem cells derived from Angelman syndrome individuals. When delivered noninvasively to
Angelman syndrome model mice, this small molecule leads to brain-wide neuronal UBE3A protein expression
without observable toxicity. We hypothesize that our small molecule approach can reverse Angelman
syndrome phenotypes in mice, justifying its advance towards additional safety studies and future clinical trials.
Towards developing this approach as a non-invasive treatment for Angelman syndrome, we propose to (1)
establish rescue of behavioral and electrophysiological phenotypes in Angelman syndrome model mice, (2)
identify the mechanism of action by which our small molecule produces unsilencing of paternal UBE3A, and (3)
perform structure-activity-relationship studies to improve efficacy and maximize favorable pharmacology. By
advancing the first small molecule treatment of Angelman syndrome, this research may lead to therapy yielding
profound lifelong benefits for this patient population.

## Key facts

- **NIH application ID:** 10847408
- **Project number:** 5R01NS131615-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Jeffrey Aube
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $558,226
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10847408

## Citation

> US National Institutes of Health, RePORTER application 10847408, Small Molecule Therapeutic Discovery for Angelman Syndrome (5R01NS131615-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10847408. Licensed CC0.

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