# Application of a novel dCasNano-based Epigenetic Editing to Treat Rett Syndrome

> **NIH NIH R43** · EPITOR THERAPEUTICS, INC. · 2024 · $698,459

## Abstract

Abstract
 Rett Syndrome is a devastating neurodevelopmental disease caused by loss of function mutations of the
MeCP2 gene, located on the X chromosome. Affecting nearly 20,000 girls in the US and EU, disease manifestation
is due to neuronal mosaicism caused by random X inactivation: half Rett patient neurons express the wild type
(WT) gene on the active X chromosome (Xa), while the other half express the mutated (MT) MeCP2 gene, with the
WT MeCP2 silenced on the inactive X chromosome (Xi).
 Epigenome editing using CRISPR systems is a potential targeted therapy allowing reactivation of the
silenced but functional MeCP2 gene on Xi. The epigenetic editor is comprised of a catalytically dead Cas (dCas)
fused with effector proteins, such as the DNA demethylase Ten-eleven translocation (TET) protein to demethylate
and thereby activate target genes. Epitor Therapeutics is developing novel epigenome editing tools to treat Rett
Syndrome. Our editor combines CasNano, an ultracompact CRISPR protein retaining robust DNA targeting, fused
to TETmini, a miniature yet potent TET demethylase domain. Compact enough to package into a single adeno-
associated virus (AAV), this epigenetic editor enables targeted delivery of epigenome editing machinery to the
brain.
 Our proposed strategy includes optimizing the epigenetic editor components for DNA targeting ability and
specificity (Aim 1); assessing in vitro target validation in Rett patient iPSC-derived neurons and off-target analysis
in human embryonic stem cells (Aim 2); and assessing pharmacology and phenotypic efficacy of the AAV9
encapsulating dCasNano-TETmini epigenetic editors in a Rett syndrome, female MeCP2-humanized mouse model
(Aim 3). If successful, this would represent the first epigenetic editing treatment for disorders of the CNS,
overcoming key delivery barriers that have blocked development of targeted epigenetic therapies.

## Key facts

- **NIH application ID:** 11008487
- **Project number:** 1R43NS139830-01
- **Recipient organization:** EPITOR THERAPEUTICS, INC.
- **Principal Investigator:** Yi-Ting Tsai
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $698,459
- **Award type:** 1
- **Project period:** 2024-09-15 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11008487

## Citation

> US National Institutes of Health, RePORTER application 11008487, Application of a novel dCasNano-based Epigenetic Editing to Treat Rett Syndrome (1R43NS139830-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11008487. Licensed CC0.

---

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