Credit: Philip Patenall/Macmillan Publishers Limited

Targeted gene therapy that delivers functional aspartoacylase (ASPA) to oligodendrocytes may be sufficient to treat Canavan disease, according to new research in mice.

Canavan disease is a rare neurometabolic disease of the white matter that is associated with toxic accumulation of N-acetylaspartate (NAA) and presents with disrupted development, macrocephaly, seizures, CNS vacuolization and hypomyelination. NAA is produced by N-acetylaspartate synthetase (NAT8L) and is catabolized by ASPA; in Canavan disease, missense mutations abrogate the function of ASPA, resulting in NAA accumulation. To date, gene therapy to replace the faulty ASPA gene in patients with Canavan disease has not met clinical expectations.

“We created two new mouse models of Canavan disease to model different pathological aspects: excess NAA levels produced in CNS neurons, or deletion of the ASPA gene in oligodendrocytes,” explains corresponding author Georg von Jonquieres. “We identified oligodendrocytes as the natural cellular target for Canavan disease gene therapy.”

targeted oligodendroglial ASPA gene therapy reverted established Canavan disease in a mouse model

Using these models, the team found that eliminating ASPA from oligodendrocytes, specifically, was sufficient to elicit a Canavan-like disease, comparable to disease induced by whole-body ASPA deficiency. Furthermore, transgenic mice that overexpressed NAT8L were neurologically normal, suggesting that supraphysiological levels of NAA in the brain are uncoupled from pathology. Interestingly, complete loss of NAA caused by NAT8L deficiency was associated with neurological abnormalities, suggesting that complete abrogation of NAA synthesis is not desirable.

On the basis of these findings, the researchers designed a gene therapy approach to specifically deliver functional ASPA to oligodendrocytes. “Our approach employed somatic gene transfer using recombinant adeno-associated virus (AAV),” comments corresponding author Matthias Klugmann. “AAV serotypes readily infect cells of all lineages in the brain and subsequent ASPA transgene expression can be limited to oligodendrocytes using cellular promotors in the AAV expression cassette.”

Remarkably, this targeted oligodendroglial ASPA gene therapy reverted established Canavan disease in a mouse model. This study opens new avenues for the development of a gene therapy for Canavan disease.