Canavan disease, a leukodystrophy caused by loss-of-function ASPA mutations, is characterized by brain dysmyelination, vacuolation, and astrogliosis (“spongiform leukodystrophy”). ASPA encodes aspartoacylase, an oligodendroglial enzyme that cleaves the abundant brain amino acid N-acetyl-L-aspartate (NAA) to L-aspartate and acetate. Aspartoacylase deficiency results in a 50% or greater elevation in brain NAA concentration ([NAA B ]). Prior studies showed that homozygous constitutive knockout of Nat8l, the gene encoding the neuronal NAA synthesizing enzyme N-acetyltransferase 8-like, prevents aspartoacylase-deficient mice from developing spongiform leukodystrophy. We now report that brain Nat8l knockdown elicited by intracerebroventricular/intracisternal administration of an adeno-associated viral vector carrying a short hairpin Nat8l inhibitory RNA to neonatal aspartoacylase-deficient Aspa Nur7/Nur7 mice lowers [NAA B ] and suppresses development of spongiform leukodystrophy. Prior studies demonstrated that constitutive Nat8l knockout prevents aspartoacylase-deficient mice from developing spongiform leukodystrophy. Bannerman et al. now report that neonatal intracerebroventricular/intracisternal administration of an adeno-associated viral vector carrying an Nat8l inhibitory short hairpin RNA preserves motor function and suppresses spongiform leukodystrophy in 3-month-old aspartoacylase-deficient mice.
Bannerman, P., Guo, F., Chechneva, O., Burns, T., Zhu, X., Wang, Y., … Pleasure, D. (2018). Brain Nat8l Knockdown Suppresses Spongiform Leukodystrophy in an Aspartoacylase-Deficient Canavan Disease Mouse Model. Molecular Therapy, 26(3), 793–800. https://doi.org/10.1016/j.ymthe.2018.01.002