Immune responses to AAV in a phase I study for Canavan disease.
BACKGROUND
Canavan disease is a rare leukodystrophy with no current treatment. rAAV-ASPA has been developed for gene delivery to the central nervous system (CNS) for Canavan disease. This study represents the first use of a viral vector in an attempt to ameliorate a neurodegenerative disorder.


METHODS
Subjects received intracranial infusions via six cranial burr holes. Adeno-associated virus, serotype 2 (AAV2), mediated intraparenchymal delivery of the human aspartoacylase cDNA at a maximum dose of 1 x 10(12) vector genomes per subject. The immune response and safety profiles were monitored in the follow-up of ten subjects.


RESULTS
Following rAAV2 administration, we found no evidence of AAV2 neutralizing antibody titers in serum for the majority of subjects tested (7/10). In a subset (3/10) of subjects, low to moderately high levels of AAV2 neutralizing antibody with respect to baseline were detected. In all subjects, there were minimal systemic signs of inflammation or immune stimulation. In subjects with catheter access to the brain lateral ventricle, cerebrospinal fluid was examined and there was a complete absence of neutralizing antibody titers with no overt signs of brain inflammation.


CONCLUSIONS
rAAV2 vector administration to the human CNS appears well tolerated. The low levels of immune response to AAV2 detected in 3/10 subjects in this study suggest at this dose and with intraparenchymal administration this approach is relatively safe. Long-term monitoring of subjects and expansion to phase II/III will be necessary in order to make definitive statements on safety and efficacy.
Department of Surgery, Division of Neurosurgery, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 401 Haddon Avenue, Camden, NJ 08103, USA.
S W J
SW
McPhee
C G
CG
Janson
C
C
Li
R J
RJ
Samulski
A S
AS
Camp
J
J
Francis
D
D
Shera
L
L
Lioutermann
M
M
Feely
A
A
Freese
P
P
Leone
D000581:Amidohydrolases / Q000172:deficiency / Q000235:genetics; D000914:Antibodies, Viral / Q000097:blood; D001921:Brain; D017825:Canavan Disease / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood; D000229:Dependovirus / Q000235:genetics / Q000276:immunology*; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D008297:Male; D009500:Neutralization Tests; D012449:Safety
D000914:Antibodies, Viral; D016207:Cytokines; D000581:Amidohydrolases; C019751:aspartoacylase