Premium
Pre‐existing immunity to adeno‐associated virus (AAV)2 limits transgene expression following intracerebral AAV2‐based gene delivery in a 6‐hydroxydopamine model of Parkinson's disease
Author(s) -
Janelidze Shorena,
Nordström Ulrika,
Kügler Sebastian,
Brundin Patrik
Publication year - 2014
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.2779
Subject(s) - adeno associated virus , transgene , microglia , genetic enhancement , biology , gene delivery , immune system , neutralizing antibody , virology , viral vector , immunology , antibody , neuroinflammation , medicine , vector (molecular biology) , gene , inflammation , recombinant dna , biochemistry
Abstract Background Adeno‐associated virus (AAV) vectors are used to deliver potentially therapeutic genes in clinical trials in Parkinson's disease (PD). Pre‐existing immunity to AAV and a local neuroinflammatory response might negatively affect the efficacy of such AAV‐mediated gene delivery. Methods We pre‐immunized rats with wild‐type AAV‐2. Three months later, we created PD‐like lesions by intrastriatal injections of 6‐hydroxydopamine (6‐OHDA) in 50% of the animals. One month later, we injected AAV2 vector expressing enhanced green fluorescent protein (eGFP) in the striatum. Using immunohistochemistry, we assessed eGFP expression, microglia activation and CD8 T cell infiltration. We also measured AAV‐2 specific neutralizing antibody titers in the serum. Results The number of striatal cells transduced with AAV2 vector expressing eGFP was reduced by 71% in rats pre‐immunized with wild‐type AAV2 compared to non‐immunized animals. We detected elevated numbers of OX6 + activated microglia in the striatum and circulating AAV2‐specific neutralizing antibodies in pre‐immunized rats. We also observed that the intrastriatal 6‐OHDA injection promoted CD8 + T cell infiltration and enhanced microglia activation. Nevertheless, the 6‐OHDA lesion did not alter AAV2‐mediated expression of eGFP in either pre‐immunized or non‐immunized rats. Conclusions Our findings indicate that intracerebral AAV2‐based gene therapy is compromised in rats with pre‐existing immunity to AAV2. By contrast, a local neuroinflammatory response, caused by intrastriatal a 6‐OHDA injection, does not affect viral vector‐mediated transgene expression. Our results emphasize the importance of monitoring circulating AAV‐specific neutralizing antibodies in patients undergoing intracerebral gene therapy using AAV vectors. Copyright © 2014 John Wiley & Sons, Ltd.