Immunological aspects of recombinant adeno-associated virus delivery to the mammalian brain.
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.
Functional Genomics and Translational Neuroscience Laboratory, Division of Molecular Medicine, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
Mihail Y
MY
Mastakov
Kristin
K
Baer
C Wymond
CW
Symes
Claudia B
CB
Leichtlein
Robert M
RM
Kotin
Matthew J
MJ
During
D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D000956:Antigens, Viral / Q000235:genetics; D001921:Brain / Q000276:immunology* / Q000821:virology*; D002213:Capsid / Q000235:genetics; D000229:Dependovirus / Q000235:genetics* / Q000276:immunology*; D015870:Gene Expression; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D007267:Injections; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D009500:Neutralization Tests; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000235:genetics; D011995:Recombination, Genetic; D013997:Time Factors; D014161:Transduction, Genetic
D000914:Antibodies, Viral; D000956:Antigens, Viral; D008164:Luminescent Proteins; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins