# Epigenome Editing Technologies for Treating Diverse Disease

> **NIH NIH U01** · DUKE UNIVERSITY · 2021 · $398,705

## Abstract

The recent revolution in novel nucleic acid-targeting systems has generated incredible opportunities for treating
disease by targeted manipulation of DNA and RNA. While the emphasis thus far has largely been on genome
editing to treat rare, inherited disorders, this represents only one mechanism by which these DNA-targeting
tools can be applied to improve human health. In fact, a significantly broader set of pathologies can be
addressed by modulating gene regulation and epigenetic states, in contrast to altering underlying DNA
sequences. Moreover, this approach has a number of advantages with respect to efficiency, safety, and
reversibility. While several studies have demonstrated proof-of-principle that in vivo somatic cell epigenome
editing can be used to program cell phentoypes and modulate therapeutic targets, there are a number of
challenges that must be overcome to prepare this technology for treatment of human disease. First, an ideal
DNA-targeting system that is facile and broadly applicable has yet to be developed. While CRISPR-Cas9
systems have dramatically transformed genome engineering, their application for human epigenome editing is
limited by specificity, incompatibility with size-restricted viral vectors, and pre-existing immunity in the human
population. Therefore, we will mine bacterial genomes for novel small CRISPR-Cas9/Cas12 systems that meet
these criteria for in vivo epigenome editing. We will examine genome-wide specificity of epigenomic
modifications with unbiased assays and assess both induced immunity in mouse models and pre-existing
immunity in human samples. Second, it remains unclear in the field of epigenome editing which epigenetic
modifications are necessary and sufficient to achieve desired outcomes in gene expression and genome
structure. We will complete a comprehensive analysis of the relationship between epigenetic states and
epigenome editing activity to develop a set of rules for achieving corresponding changes in gene expression.
Finally, we will validate these epigenome editing tools in vivo in a set of pilot experiments in mouse models of
neuromuscular disease encompassing a representative set of epigenomic states. In close collaboration with
the Somatic Cell Genome Editing Consortium, this work will prepare epigenome editing technology for human
clinical translation in which it may have a transformative effect on a broad array of both rare and common
disease.

## Key facts

- **NIH application ID:** 10214461
- **Project number:** 5U01AI146356-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Charles A. Gersbach
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $398,705
- **Award type:** 5
- **Project period:** 2019-07-08 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10214461

## Citation

> US National Institutes of Health, RePORTER application 10214461, Epigenome Editing Technologies for Treating Diverse Disease (5U01AI146356-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10214461. Licensed CC0.

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