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.
Canavan disease is a leukodystrophy of infancy and childhood characterized by elevated brain levels of N-acetyl-L-aspartate (NAA), early onset brain vacuolar degeneration, and delayed brain neuron depletion. There are currently no effective therapies for Canavan disease. We will test whether suppressing brain NAA synthesis, or inhibiting astroglial NAA transport, will reverse pre- existing leukodystrophy and prevent progressive neuron loss in a well characterized mouse Canavan disease model.
