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Immune responses to AAV in a phase I study for Canavan disease
Author(s) -
McPhee S. W. J.,
Janson C. G.,
Li C.,
Samulski R. J.,
Camp A. S.,
Francis J.,
Shera D.,
Lioutermann L.,
Feely M.,
Freese A.,
Leone P.
Publication year - 2006
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.885
Subject(s) - medicine , immune system , neutralizing antibody , adeno associated virus , antibody titer , immunology , antibody , titer , vector (molecular biology) , biology , biochemistry , gene , recombinant dna
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 × 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. Copyright © 2006 John Wiley & Sons, Ltd.