Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain.
This clinical protocol describes virus-based gene transfer for Canavan disease, a childhood leukodystrophy. Canavan disease, also known as Van Bogaert-Bertrand disease, is a monogeneic, autosomal recessive disease in which the gene coding for the enzyme aspartoacylase (ASPA) is defective. The lack of functional enzyme leads to an increase in the central nervous system of the substrate molecule, N-acetyl-aspartate (NAA), which impairs normal myelination and results in spongiform degeneration of the brain. No effective treatment currently exists; however, virus-based gene transfer has the potential to arrest or reverse the course of this otherwise fatal condition. This procedure involves neurosurgical administration of approximately 900 billion genomic particles (approximately 10 billion infectious particles) of recombinant adeno-associated virus (AAV) containing the aspartoacylase gene (ASPA) directly to affected regions of the brain in each of 21 patients with Canavan disease. Pre- and post-delivery assessments include a battery of noninvasive biochemical, radiological, and neurological tests. This gene transfer study represents the first clinical use of AAV in the human brain and the first instance of viral gene transfer for a neurodegenerative disease.
Janson
Christopher
C
Robert Wood Johnson Medical School-UMDNJ and Cooper Hospital, 08103, USA.
McPhee
Scott
S
Bilaniuk
Larissa
L
Haselgrove
John
J
Testaiuti
Mark
M
Freese
Andrew
A
Wang
Dah-Jyuu
DJ
Shera
David
D
Hurh
Peter
P
Rupin
Joan
J
Saslow
Elizabeth
E
Goldfarb
Olga
O
Goldberg
Michael
M
Larijani
Ghassem
G
Sharrar
William
W
Liouterman
Larisa
L
Camp
Angelique
A
Kolodny
Edwin
E
Samulski
Jude
J
Leone
Paola
P
D000581:Amidohydrolases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D017825:Canavan Disease / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D002675:Child, Preschool; D002985:Clinical Protocols; D002986:Clinical Trials as Topic; D015331:Cohort Studies; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D007223:Infant; D007276:Injections, Intraventricular; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D018579:Patient Selection
D000581:Amidohydrolases; C019751:aspartoacylase