# Gene editing in the brain with CRISPR-PEG

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $671,929

## Abstract

CRISPR-based gene editing has the potential to revolutionize the treatment of genetic brain disorders. However,
complications with brain delivery have limited the utility of CRISPR-based therapeutics. To address this critical
need, we have developed a new gene editing delivery vehicle, termed CRISPR-PEG, which is composed of Cas9
RNP conjugated to polyethylene glycol (PEG). CRISPR-PEG has tremendous promise as a delivery vehicle
because of its excellent biocompatibility, the well-established clinical track record of PEG, and its enhanced tissue
diffusion capability in comparison to nanoparticles. Our preliminary results demonstrate that CRISPR-PEG delivers
and edits neurons efficiently in the motor cortex or striatum in mice; after an intracranial injection, neurons were
edited with a high specificity (45~85%). Notably, CRISPR-PEG also edited neurons in the olfactory bulb after
intranasal administration. These exciting results demonstrate that CRISPR-PEG has great potential as bio-tool, and
as a platform for developing therapeutics. In this proposal we will test our novel delivery vehicle CRISPR-PEG in
fragile X syndrome (FXS). We have selected FXS as a test bed for CRISPR-PEG because it is the most common
inherited cause of intellectual disability with no treatment available. In addition, FXS has a monogenic cause,
namely expanded CGG repeats>200 and hypermethylation in the FMR1 promoter region, which causes silencing of
the fragile X mental retardation 1 (FMR1) gene. Therefore, the central objectives of this proposal are (1) to test
CRISPR-PEG in brain disorders by targeting FXS-associated genes, and (2) to develop new CRISPR-PEG variants
with improved diffusion and efficiency. The central hypothesis is: the novel non-viral delivery vehicle CRISPR-
PEG will deliver Cas9 RNPs into the brain, efficiently edit FXS-associated genes in neurons, and rescue mice from
multiple FXS-associated phenotypes. The central objective will be accomplished by completing the following
specific aims.
Specific Aim 1. Knock down mGluR5 using CRISPR-PEG in the mouse model of FXS as proof of principle.
Specific Aim 2. Reactivate FMR1 gene expression using CRISPR-PEG.
Specific Aim 3. Develop CRISPR-PEGs that diffuse throughout the brain and edit brain tissue efficiently.
 At the completion of this proposed study, we will have developed an efficient strategy for gene editing neurons
using a novel non-viral delivery vehicle CRISPR-PEG. Our proposed studies are significant because the results
will provide the basis for developing therapeutics for FXS and fragile X-associated disorders caused by FMR1
deficiency. Moreover, we will develop a non-viral-based vehicle that can edit large volumes of brain tissue after a
single injection. The experiments in this proposal are highly innovative because we will have developed an efficient
and safe non-viral delivery vehicle, which will greatly advance the field of neuroscience and CRISPR-based
therapeutics.

## Key facts

- **NIH application ID:** 10770404
- **Project number:** 5R01MH125979-04
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Hye Young Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $671,929
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10770404

## Citation

> US National Institutes of Health, RePORTER application 10770404, Gene editing in the brain with CRISPR-PEG (5R01MH125979-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10770404. Licensed CC0.

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