PROJECT SUMMARY
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 µM - 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.