# Nanoparticle-mediated delivery of a base editor for in utero treatment of Canavan Disease

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $423,939

## Abstract

ABSTRACT
Canavan disease is a rare genetic neurological disorder characterized by a vacuolar (spongiform)
leukodystrophy caused by ASPA mutations that diminish brain aspartoacylase activity.
Neonatal/infantile Canavan disease is the most common and most severe form of the condition.
Affected infants appear normal for the first few months of life, but problems with development become
noticeable by age 3 to 5 months. These infants usually do not develop motor skills such as turning over,
controlling head movement, and sitting without support. Other characteristics of this condition include
hypotonia, macrocephaly, and irritability. There is no cure, nor is there a standard course of treatment.
The symptomatic support for this neurodegenerative disorder includes dietary manipulations,
administration of lithium citrate and anticonvulsants, and AAV-mediated brain parenchymal ASPA gene
therapy, yet, these treatments do not reverse or prevent the progression of neurological deficits in
affected infants and children. To address this unmet medical need, we propose to develop an innovative
treatment comprised of an in utero delivery of solid lipid nanoparticle (LNP)/mRNA complexes by
intraventricular injection that will target and edit oligodendrocyte before birth, correct ASAP mutations,
and restore aspartoacylase expression in patients influenced by point mutations. Gene editing at the in
utero stage has great potential to cure neurological disorders, including Canavan disease before
symptoms are unset. Our preliminary studies demonstrated that in utero intraventricular delivery LNP
mRNA complexes can efficiently deliver mRNA to the brain and spinal cord tissue. These experiments
are the first demonstration of mRNA based nonviral gene editing in utero and open up numerous
therapeutic applications, given the tremendous versatility of mRNA. The central hypothesis of this
proposal is that: LNPs will deliver mRNA for gene editing enzymes in utero and will rescue mice from
Canavan disease at and after birth. This hypothesis is based upon our preliminary data demonstrating
that LNPs containing CRE can safely and efficiently transfect oligodendrocyte in the brain of Ai9 mice
after in utero intraventricular delivery. The central objective of this study is to develop LNP formulations
that can efficiently edit oligodendrocyte in utero and develop a strategy for treating Canavan disease.

## Key facts

- **NIH application ID:** 10727872
- **Project number:** 1R21NS133881-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** David E. Pleasure
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $423,939
- **Award type:** 1
- **Project period:** 2023-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10727872

## Citation

> US National Institutes of Health, RePORTER application 10727872, Nanoparticle-mediated delivery of a base editor for in utero treatment of Canavan Disease (1R21NS133881-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10727872. Licensed CC0.

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