# Development of NAT8L inhibitors for the Treatment of Canavan Disease

> **NIH NIH R61** · JOHNS HOPKINS UNIVERSITY · 2024 · $396,324

## Abstract

PROJECT SUMMARY
Canavan disease (CD) is an autosomal recessive inherited leukodystrophy caused by the mutations in ASPA
gene encoding the aspartoacylase enzyme, leading to loss of enzyme activity and increased concentrations of
its substrate N-acetylaspartate (NAA) in the brain. The abnormally high levels of NAA result in spongiform
degeneration of white matter, aberrant myelination, brain edema, macrocephaly, and severe cognitive and motor
deficits. Currently, there is no cure or disease-modifying treatment for CD. There is an urgent need for effective
therapies for patients with CD. Aspartate N-acetyltransferase encoded by the NAT8L gene catalyzes
biosynthesis of NAA from aspartate and acetyl-CoA. We and others postulated that brain-penetrant NAT8L
inhibitors could reduce brain NAA levels and alleviate the NAA-driven pathology in CD. Indeed, genetic disruption
of NAT8L in CD mouse model (Aspanur7nur7) was found to show strong therapeutic benefit. Currently, however,
there are no small molecule NAT8L inhibitors that penetrate the blood-brain barrier. Through a large HTS
screening campaign followed by preliminary medicinal chemistry efforts, however, our team identified a novel
sub-micromolar and brain penetrant NAT8L inhibitor structurally distinct from previously reported inhibitors. To
capitalize on this discovery, herein we propose to advance this project to the next stage, where the focus will be
on optimizing the lead compound for desirable pharmacological properties (R61 Phase), enabling in vivo efficacy
studies in a murine model of CD (R33 Phase). We are poised to seize this opportunity and establish in vivo proof
of concept using a potent, selective, brain-penetrable NAT8L inhibitor to treat CD by executing the following
three Specific Aims: (R61 Phase Aim 1) Conduct structure-activity relationship (SAR) studies on the lead NAT8L
inhibitor; (R61 Phase Aim 2) Conduct in vitro characterization and in vivo pharmacokinetic/pharmacodynamic
(PK/PD) profiling of potent NAT8L inhibitors from Aim 1; (R33 Phase Aim 3) Assess in vivo efficacy of the
optimized NAT8L inhibitor in an established murine model of CD.

## Key facts

- **NIH application ID:** 10872391
- **Project number:** 1R61NS136652-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Barbara Stauch Slusher
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $396,324
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872391

## Citation

> US National Institutes of Health, RePORTER application 10872391, Development of NAT8L inhibitors for the Treatment of Canavan Disease (1R61NS136652-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10872391. Licensed CC0.

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