Canavan disease (CD) is rare autosomal recessive leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to loss of enzyme activity and increased concentrations of the substrate N-acetylaspartate (NAA) in the brain. Accumulation of brain NAA results in spongiform degeneration of white matter, aberrant myelination, brain edema, macrocephaly, severe cognitive and motor deficits and ultimately death. There is no cure, nor is there a standard course of treatment for CD. Treatment is currently limited to supportive care and symptom management. Genetic deletion of the ASPA gene in mice has been shown to reproduce many of the CD disease symptoms seen in patients. Important to this proposal, deletion of the gene encoding for aspartate N-acetyltransferase 8 (NAT8L), the enzyme that catalyzes the biosynthesis of NAA from aspartate and acetyl CoA, prevented leukodystrophy in a CD mouse model. These mice showed substantial reduction in NAA levels and no evidence of astroglial vacuolation, astrogliosis, or demyelination in the cerebellum or forebrain. Similar therapeutic benefits were observed with intracisternal administration of antisense oligonucleotide to NAT8L. These results strongly suggest that inhibition of NAT8L would be useful in the treatment of CD. Currently, however, there are no NAT8L inhibitors that are clinically available; known NAT8L inhibitors have low potency (IC50 values in the ?M - mM range) and/or possess carboxylate moieties that prevent brain penetration. This proposal aims to conduct high throughput screening (HTS) of a large and diverse 400,000 compound library for small molecule inhibitors of human NAT8L. Successful identification of tractable hit compounds followed by preliminary structural optimization should lead to the discovery of promising lead NAT8L inhibitors with potential for future development of therapeutics for CD. We are poised to seize this opportunity by executing the following three Specific Aims:
(Aim 1) conduct NAT8L HTS and hit confirmation assays;
(Aim 2) conduct hit clustering, preliminary SAR, and ADME profiling;
(Aim 3) conduct preliminary lead optimization.

Public Health Relevance

Canavan disease is a autosomal recessive neurological disorder and one of the most prevalent degenerative cerebral diseases of infancy. The disease is caused by genetic deficiency of the aspartoacylase (ASPA) enzyme resulting in the accumulation of brain N-acetylaspartate (NAA) and deterioration of white matter (myelin) which prevents normal neurotransmission. There are currently no treatments. This project proposes to identify novel small molecule drugs that prevent the formation of NAA by inhibiting its synthesis by N-acetyltransferase 8-like (NAT8L), with the underlying goal of identifying a new therapeutic strategy for Canavan disease patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Roof, Rebecca
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Johns Hopkins University
Schools of Medicine
United States
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