# Advancing an XIST ASO candidate for the treatment of Rett Syndrome

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $787,051

## Abstract

PROJECT SUMMARY
Rett Syndrome (RTT) is a severe neurodevelopmental disorder with an incidence of 1 in ~10,000 girls
throughout the world. It is caused by a single gene mutation of the X-linked methyl-CpG-binding protein 2
(MECP2), a chromatin-associated gene product that is crucial for neuronal development. There is presently no
disease-specific treatment or cure. Despite its single-gene nature, finding a treatment for Rett Syndrome has
proven challenging. Previous studies showed that, in mice, restoring MECP2 expression using genetic
methods can reverse the disease symptoms. The reversal has provided hope that doing the same using
pharmacological methods could treat and possibly cure Rett Syndrome in patients. RTT girls carry one mutant
MECP2 allele and one normal allele. In half of their cells, the mutant copy is expressed while the normal copy
lies dormant because of X-chromosome inactivation. In the proposed project of this application, the laboratory
will employ an “X-reactivation” strategy (previously developed by the laboratory) to restore expression of
MECP2 from the inactivated X-chromosome. The strategy uses an antisense oligonucleotides (ASO) directed
against XIST RNA, the master regulator of X-chromosome silencing, combined with priming by a small
molecule inhibitor of DNA methylation. In the first funding cycle of R01-MH118351, research results show that
the X-reactivation technology can restore endogenous MECP2 protein expression in the brain and rescue RTT
symptoms in a disease-relevant animal model. The proposed research for cycle 2 will focus on (i) completing
PK/PD studies, optimizing dosing schedules, and determining an ideal intervention window in a mouse model,
and (ii) optimizing the human XIST ASO, performing toxicology studies, and nominating 2-3 development
candidates for IND-enabling studies.

## Key facts

- **NIH application ID:** 10879590
- **Project number:** 2R01MH118351-06
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** JEANNIE T LEE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $787,051
- **Award type:** 2
- **Project period:** 2019-07-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879590

## Citation

> US National Institutes of Health, RePORTER application 10879590, Advancing an XIST ASO candidate for the treatment of Rett Syndrome (2R01MH118351-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10879590. Licensed CC0.

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