# Novel Gene Therapy Strategies for Canavan Disease

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $459,292

## Abstract

ABSTRACT
 Canavan disease (CD) is a rare childhood leukodystrophy caused by autosomal recessive mutations in
the aspartoacylase (ASPA) gene. Deficiency of ASPA in Canavan patients leads to the accumulation of N-
Acetyl-Aspartic Acid (NAA), resulting in swelling and spongy degeneration of white matter in the brain. The
clinical manifestations of this fatal disease include psychomotor retardation, muscular hypotonia,
macrocephaly, head lag, seizures, and early death. Synthesis of NAA is carried out in the mitochondria of
neurons by N-acetyltransferase-8-like (NAT8L) and hydrolyzed in oligodendrocytes by ASPA. Gene
replacement therapy for ASPA deficiency is currently the most promising strategy for treating CD. Notably, we
have recently achieved full therapeutic correction of the Canavan phenotype in the Aspa knockout (CD-KO)
mouse model. A single intravenous injection of recombinant adeno-associated virus packaged with the human
ASPA transgene (rAAV-hASPA) at early ages completely resolves neuropathology, resulting in treated animals
that outperform wild-types in motor function tests. However, based on strong preliminary evidence, we now
hypothesize that the CD phenotype presents a secondary etiology related to metabolism dysfunction. In
addition, we recently revealed that overexpression of ASPA in wild type cells in vitro resulted in abnormal
mitochondrial shape and function. These findings necessitate further preclinical investigations that focus on: 1)
characterizing the possible toxicity of ASPA overexpression in cell types of the CNS and peripheral organs, 2)
developing ASPA regulatory cassette(s) that can mimic endogenous physiological levels of ASPA to
circumvent adverse effects that may exist due to treatment, and 3) determining the physiological and
behavioral effects of ASPA overexpression using a clinically relevant non-human primate model. Our new
research strategy now builds on our current promising progress and advances our goals for a safe and
effective gene therapy for CD.

## Key facts

- **NIH application ID:** 10109151
- **Project number:** 5R01NS076991-08
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Guangping Gao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $459,292
- **Award type:** 5
- **Project period:** 2012-09-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10109151

## Citation

> US National Institutes of Health, RePORTER application 10109151, Novel Gene Therapy Strategies for Canavan Disease (5R01NS076991-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10109151. Licensed CC0.

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