# Manipulating N-acetyl-L-aspartate to reverse Canavan leukodystrophy

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $431,750

## Abstract

Canavan disease is an as yet incurable leukodystrophy of infancy and childhood, in which ASPA
mutations prevent brain expression of functional aspartoacylase. Aspartoacylase is required for
cleavage of the abundant brain amino acid N-acetyl-L-aspartate (NAA); hence, the brain
concentration of NAA becomes massively elevated in Canavan disease. This project will evaluate
the fundamental hypothesis that brain maldistribution of excess NAA in Canavan disease causes
brain vacuolar degeneration and leads to delayed brain neuron loss. Our prior work provided
some support for this hypothesis; we reported that constitutive deletion or neonatal brain
knockdown of Nat8l, which encodes the neuronal NAA-synthesizing enzyme N-acetyltransferase
8-like, prevents aspartoacylase-deficient Canavan model mouse pups from developing vacuolar
leukodystrophy. And, in preliminary studies, we’ve shown that intracisternal administration of an
anti-Nat8l single-stranded locked nucleic acid antisense oligonucleotide (“Nat8l gapmer”) to
young adult Canavan model mice reverses their pre-existing ataxia and vacuolar cerebellar
degeneration. Specific Aim 1 will determine whether an Nat8l gapmer-based treatment regimen
can be devised that will provide adult Canavan model mice with long-term protection against
vacuolar leukodystrophy and neuron loss. If so, this approach might be translatable to infants
and children with symptomatic Canavan disease. Specific Aim 2 focuses on the hypothesis that
vacuolar leukodystrophy in Canavan model mice is preventable and reversible by inhibiting
astroglial over-accumulation of NAA. We will test a prediction, based on this hypothesis, that
vacuolar leukodystrophy in Canavan model mice can be prevented or reversed, respectively, by
constitutive or astroglial conditional Slc13a3 deletion; Slc13a3 encodes a plasma membrane
sodium-coupled dicarboxylate cotransporter (NaDC3) expressed by astroglia that has high affinity
for NAA. A positive result in this aim would identify Slc13a3 and NaDC3 as novel Canavan
disease therapeutic targets.

## Key facts

- **NIH application ID:** 10026520
- **Project number:** 1R21NS117386-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** David E. Pleasure
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $431,750
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10026520

## Citation

> US National Institutes of Health, RePORTER application 10026520, Manipulating N-acetyl-L-aspartate to reverse Canavan leukodystrophy (1R21NS117386-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10026520. Licensed CC0.

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