title: The influence of epileptic neuropathology and prior peripheral immunity on CNS transduction by rAAV2 and rAAV5.
abstract: Adeno-associated virus (AAV) provides a promising platform for clinical treatment of neurological disorders owing to its established efficacy and lack of apparent pathogenicity. To use viral vectors in treating neurological disease, however, transduction must occur under neuropathological conditions. Previous studies in rodents have shown that AAV5 more efficiently transduces cells in the hippocampus and piriform cortex than AAV2. Using the kainic acid (KA) model of temporal lobe epilepsy and AAV2 and 5 carrying a hybrid chicken β-actin promoter driving green fluorescent protein (GFP), we found that limbic seizure activity caused substantial neuropathology and resulted in a significant reduction in subsequent AAV5 transduction. Nonetheless, this reduced transduction still was greater than AAV2 transduction in control rats. Although KA seizures compromise blood-brain barrier function, potentially increasing exposure of target tissue to circulating neutralizing antibodies, we observed no interaction between KA seizure-induced damage and immunization status on AAV transduction. Finally, while we confirmed the near total neuronal-specific transgene expression for both serotypes in control rats, AAV5-GFP expression was increasingly localized to astrocytes in seizure-damaged areas. Thus, the pathological milieu of the injured brain can reduce transduction efficacy and alter viral tropism- both relevant concerns when considering viral vector gene therapy for neurological disorders.
authors.affiliation: UNC Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Weinberg
authors.forename: B L
authors.initials: BL
authors.lastname: Blake
authors.forename: R J
authors.initials: RJ
authors.lastname: Samulski
authors.forename: T J
authors.initials: TJ
authors.lastname: McCown
mesh_terms: D000199:Actins / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D001253:Astrocytes / Q000378:metabolism; D000229:Dependovirus; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000276:immunology / Q000473:pathology* / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000627:therapeutic use*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014161:Transduction, Genetic / Q000379:methods*
chemical_list: D000199:Actins; D057134:Antibodies, Neutralizing; D049452:Green Fluorescent Proteins; D007608:Kainic Acid