Gene therapy for Canavan's disease takes a step forward

Abstract

Canavan's disease (CD) is a rare but devastating pediatric leukodystrophy that causes progressive spongy neurodegeneration and is invariably fatal in congenital form.1 The disease is associated with >54 loss-of-function mutations2,3,4 in the enzyme aspartoacylase (ASPA), leads to accumulation of the substrate N-acetyl aspartic acid (NAA) in the brain, and is diagnosed via the presence of NAA aciduria.1 CD is characterized by dysmyelination, intramyelinic edema (leading to hydrocephalus), and extensive vacuolation of the central nervous system (CNS) white matter.5 Currently there is no established therapy that affects progression of the disease, and survival is based primarily on improved general medical care. A previous gene therapy attempt using liposome-encapsulated plasmid DNA6 had shown encouraging although transient decreases in local NAA concentrations in the treated brains, which prompted a gene therapy clinical protocol using recombinant AAV serotype 2 (rAAV2) in the hope of better dissemination of the vector and more sustainable NAA reductions.7 In a recent issue of Science Translational Medicine, Leone et al.8 report long-term follow-up of 13 of the 28 patients enrolled in this trial, who received intracranial injections of first-generation rAAV vectors-based on serotype 2 nearly a decade ago.