Gene replacement
therapy is a rational therapeutic strategy and clinical intervention for
neurodegenerative disorders like
Canavan disease, a leukodystrophy caused by biallelic mutations in the
aspartoacylase (ASPA) gene. We aimed to investigate whether simultaneous intravenous (i.v.) and intracerebroventricular (i.c.v.) administration of rAAV9-CB6-ASPA provides a safe and effective therapeutic strategy in an open-label, individual-patient, expanded-access trial for
Canavan disease.
Immunomodulation was given prophylactically prior to adeno-associated virus (AAV) treatment to prevent an immune response to ASPA or the vector capsid. The patient served as his own control, and change from baseline was assessed by clinical pathology tests, vector genomes in the blood,
antibodies against ASPA and AAV capsids, levels of cerebrospinal fluid (CSF)
N-acetylaspartate (NAA), brain water content and morphology, clinical status, and motor function tests. Two years post treatment, the patient's white matter myelination had increased, motor function was improved, and he remained free of typical severe
epilepsy. NAA level was reduced at 3 months and remained stable up to 4 years post treatment.
Immunomodulation prior to AAV exposure enables repeat dosing and has prevented an anti-transgene immune response. Dual-route administration of gene therapy may improve treatment outcomes.