# CONTROL OF LONG GENE EXPRESSION AS A NOVEL THERAPEUTIC APPROACH FOR RETT SYNDROME

> **NIH NIH K08** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $197,640

## Abstract

PROJECT SUMMARY:
Rett syndrome is the most common genetic cause of intellectual disability in girls and is characterized by
neurodevelopmental delay, abnormal arm movements, seizures, and autism spectrum behavior. It has been
known for nearly a decade that Rett syndrome is caused by mutations in the MECP2 gene and that restoring
normal levels of MECP2 in rodent models, even after symptom onset, can reverse most symptoms. While this
genetic insight has provided hope for treatment, the incredible complexity of MeCP2 function in neurons has
challenged the development of actionable therapeutic strategies. MeCP2 is known to be highly enriched in
neurons and bind to methylated DNA, but its subtle effects on transcription have been difficult to understand and
reconcile with the severity of Rett syndrome phenotypes. Our laboratory recently performed a meta-analysis of
nearly a dozen independent studies of MeCP2-regulated genes and found that MeCP2 selectively controls the
expression of very long genes. This observation is highly specific to MeCP2 and is observed in both rodent
models and Rett syndrome patients. The high level of MeCP2 in neurons and the tendency for neuronal proteins
to be large and encoded by long genes, may explain why MeCP2 mutations preferentially cause neuronal
dysfunction. Our preliminary data supports a role of long gene misregulation in the pathogenesis of Rett
syndrome because normalizing long gene expression directly with topoisomerase inhibitors improves Rett
phenotypes in vitro and in vivo. In neurons, topoisomerases function to unwind DNA during transcription and are
required for expression of long genes. The reciprocal control over long gene expression between MeCP2 and
topoisomerase, as well as preliminary data demonstrating a physical interaction between these proteins, raise
several important mechanistic and therapeutically relevant questions that are the focus of this proposal. 1) to
characterize the cellular and behavioral effects of topoisomerase inhibition in the mouse model of Rett
syndrome, and 2) to characterize the interaction between MeCP2 and topoisomerase. Together, these
studies aim to inform a new therapeutic strategy for Rett syndrome focused on correcting long gene misregulation
through direct control of topoisomerase activity.

## Key facts

- **NIH application ID:** 9942524
- **Project number:** 5K08NS101064-05
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** William Russell Renthal
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $197,640
- **Award type:** 5
- **Project period:** 2019-12-11 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942524

## Citation

> US National Institutes of Health, RePORTER application 9942524, CONTROL OF LONG GENE EXPRESSION AS A NOVEL THERAPEUTIC APPROACH FOR RETT SYNDROME (5K08NS101064-05). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9942524. Licensed CC0.

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