The influence of epileptic neuropathology and prior peripheral immunity on CNS transduction by rAAV2 and rAAV5

• Published in: Gene therapy Vol. 18; no. 10; pp. 961 - 968
• Main Authors: WEINBERG, M. S, BLAKE, B. L, SAMULSKIL, R. J, MCCOWN, T. J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.10.2011
• Subjects: Actin; Actins - genetics; Adeno-associated virus; Ageing, cell death; Analysis of Variance; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Antibodies, Neutralizing - immunology; Applied cell therapy and gene therapy; Astrocytes; Astrocytes - metabolism; Biological and medical sciences; Biotechnology; Blood-brain barrier; Care and treatment; Cell death; Cell physiology; Convulsions & seizures; Cortex (piriform); Cortex (temporal); Dependovirus; Epilepsy; Epilepsy, Temporal Lobe - chemically induced; Epilepsy, Temporal Lobe - immunology; Epilepsy, Temporal Lobe - pathology; Epilepsy, Temporal Lobe - therapy; Fundamental and applied biological sciences. Psychology; Gene expression; Gene therapy; Genetic aspects; Genetic Therapy - methods; Genetic Vectors - therapeutic use; Green fluorescent protein; Green Fluorescent Proteins - metabolism; Health aspects; Health. Pharmaceutical industry; Immunization; Immunohistochemistry; Industrial applications and implications. Economical aspects; Kainic acid; Kainic Acid - toxicity; Male; Medical sciences; Molecular and cellular biology; Nervous system diseases; Neurological diseases; Neurological disorders; Neuropathology; Pathogenicity; Promoter Regions, Genetic - genetics; Rats; Rats, Sprague-Dawley; Rodents; Seizures; Serotypes; Temporal lobe; Transduction; Transduction, Genetic - methods; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Tropism; Viruses; United States; Nervous system diseases; Antibody; Recombinant virus; Epilepsy; neurodegeneration; neutralizing antibodies; Immunity; glia; Cerebral disorder; Genetic transfer; neuronal cell death; Neuron; Cell death; Central nervous system disease; viral vector gene transfer; Degenerative disease; Transduction; Gene therapy; Kainic acid; Apoptosis
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2011.49

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.