title: Long-term follow-up after gene therapy for canavan disease.
abstract: Canavan disease is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to loss of enzyme activity and increased concentrations of the substrate N-acetyl-aspartate (NAA) in the brain. Accumulation of NAA results in spongiform degeneration of white matter and severe impairment of psychomotor development. The goal of this prospective cohort study was to assess long-term safety and preliminary efficacy measures after gene therapy with an adeno-associated viral vector carrying the ASPA gene (AAV2-ASPA). Using noninvasive magnetic resonance imaging and standardized clinical rating scales, we observed Canavan disease in 28 patients, with a subset of 13 patients being treated with AAV2-ASPA. Each patient received 9 × 10(11) vector genomes via intraparenchymal delivery at six brain infusion sites. Safety data collected over a minimum 5-year follow-up period showed a lack of long-term adverse events related to the AAV2 vector. Posttreatment effects were analyzed using a generalized linear mixed model, which showed changes in predefined surrogate markers of disease progression and clinical assessment subscores. AAV2-ASPA gene therapy resulted in a decrease in elevated NAA in the brain and slowed progression of brain atrophy, with some improvement in seizure frequency and with stabilization of overall clinical status.
authors.affiliation: Department of Cell Biology, Cell & Gene Therapy Center, University of Medicine & Dentistry of New Jersey, Stratford, NJ 08034, USA. leonepa@umdnj.edu
authors.forename: Paola
authors.initials: P
authors.lastname: Leone
authors.forename: David
authors.initials: D
authors.lastname: Shera
authors.forename: Scott W J
authors.initials: SW
authors.lastname: McPhee
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Francis
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Kolodny
authors.forename: Larissa T
authors.initials: LT
authors.lastname: Bilaniuk
authors.forename: Dah-Jyuu
authors.initials: DJ
authors.lastname: Wang
authors.forename: Mitra
authors.initials: M
authors.lastname: Assadi
authors.forename: Olga
authors.initials: O
authors.lastname: Goldfarb
authors.forename: H Warren
authors.initials: HW
authors.lastname: Goldman
authors.forename: Andrew
authors.initials: A
authors.lastname: Freese
authors.forename: Deborah
authors.initials: D
authors.lastname: Young
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: During
authors.forename: R Jude
authors.initials: RJ
authors.lastname: Samulski
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Janson
mesh_terms: D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D017825:Canavan Disease / Q000378:metabolism / Q000628:therapy*; D002648:Child; D002675:Child, Preschool; D015316:Genetic Therapy; D006801:Humans; D007223:Infant; D011446:Prospective Studies
chemical_list: D001224:Aspartic Acid; C000179:N-acetylaspartate