Targeted Aspartoacylase Gene Therapy Reverts Canavan Disease

RESEARCH HIGHLIGHTS

Nature Reviews Neurology | Published online 24 Nov 2017; doi:10.1038/nrneurol.2017.170

WHITE MATTER DISEASE Targeted aspartoacylase gene therapy reverts Canavan disease P h il ip P a Targeted gene therapy that delivers oligodendrocytes as the natural t e n a l functional aspartoacylase (ASPA) to cellular target for Canavan l / M

oligodendrocytes may be sufficient to disease gene therapy.” c

treat Canavan disease, according to Using these models, the l

new research in mice. team found that eliminating u

Canavan disease is a rare neuro ASPA from oligodendrocytes, h

metabolic disease of the white specifically, was sufficient to L

t matter that is associated with toxic elicit a Canavan-like disease, e accumulation of N-acetylaspartate comparable to disease induced d (NAA) and presents with disrupted by whole-body ASPA deficiency. development, macrocephaly, Furthermore, transgenic mice that seizures, CNS vacuolization and overexpressed NAT8L were neuro hypomyelination. NAA is produced logically normal, suggesting that readily infect cells of all lineages by N-acetylaspartate synthetase supraphysiological levels of NAA in in the brain and subsequent ASPA (NAT8L) and is catabolized by ASPA; the brain are uncoupled from pathol transgene expression can be limited in Canavan disease, missense muta ogy. Interestingly, complete loss of to oligodendrocytes using cellular tions abrogate the function of ASPA, NAA caused by NAT8L deficiency promotors in the AAV expression targeted resulting in NAA accumulation. To was associated with neurological cassette.” oligodendroglial date, gene therapy to replace the abnormalities, suggesting that com Remarkably, this targeted oligo ASPA gene faulty ASPA gene in patients with plete abrogation of NAA synthesis is dendroglial ASPA gene therapy Canavan disease has not met clinical not desirable. reverted established Canavan disease therapy expectations. On the basis of these findings, the in a mouse model. This study opens reverted “We created two new mouse researchers designed a gene therapy new avenues for the development of a established models of Canavan disease to model approach to specifically deliver gene therapy for Canavan disease. Canavan different pathological aspects: functional ASPA to oligodendrocytes. Shimona Starling excess NAA levels produced in “Our approach employed somatic disease in a ORIGINAL ARTICLE von Jonquieres, G. et al. CNS neurons, or deletion of the gene transfer using recombinant Uncoupling N-acetylaspartate from brain mouse model ASPA gene in oligodendrocytes,” adeno-associated virus (AAV),” pathology: implications for Canavan disease gene explains corresponding author comments corresponding author therapy. Acta Neuropathol. http://doi.org/10.1007/ s00401-017-1784-9 (2017) Georg von Jonquieres. “We identified Matthias Klugmann. “AAV serotypes