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Journal of Virology, August 2002, p. 8446-8454, Vol. 76, No. 16
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.16.8446-8454.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Immunological Aspects of Recombinant Adeno-Associated Virus Delivery to the Mammalian Brain

Mihail Y. Mastakov,1 Kristin Baer,1 C. Wymond Symes,1 Claudia B. Leichtlein,1 Robert M. Kotin,2 and Matthew J. During1,3*

Functional Genomics and Translational Neuroscience Laboratory, Division of Molecular Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand,1 Laboratory of Biochemical Genetics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892,2 CNS Gene Therapy Center, Jefferson Medical College, Philadelphia, Pennsylvania 191073

Received 28 March 2002/ Accepted 25 April 2002

Recombinant adeno-associated viruses (rAAV) are highly efficient vectors for gene delivery into the central nervous system (CNS). However, host inflammatory and immune responses may play a critical role in limiting the use of rAAV vectors for gene therapy and functional genomic studies in vivo. Here, we evaluated the effect of repeated injections of five rAAV vectors expressing different genetic sequences (coding or noncoding) in a range of combinations into the rat brain. Specifically, we wished to determine whether a specific immune or inflammatory response appeared in response to the vector and/or the transgene protein after repeated injections under conditions of mannitol coinjection. We show that readministration of the same rAAV to the CNS is possible if the interval between the first and second injection is more than 4 weeks. Furthermore, our data demonstrate that rAAV vectors carrying different genetic sequences can be administered at intervals of 2 weeks. Our data therefore suggest that the AAV capsid structure is altered by the vector genetic sequence, such that secondary structures of the single-stranded genome have an impact on the antigenicity of the virus. This study provides guidelines for more rational design of gene transfer studies in the rodent brain and, in addition, suggests the use of repeated administration of rAAV as a viable form of therapy for the treatment of chronic diseases.

* Corresponding author. Mailing address: Department of Neurosurgery, Jefferson Medical College and Thomas Jefferson University, Philadelphia, PA 19107. Phone: (215) 955-1251. Fax: (215) 955-4878. E-mail: matthew.during{at}mail.tju.edu.

Journal of Virology, August 2002, p. 8446-8454, Vol. 76, No. 16
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.16.8446-8454.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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