Neuroprotective effect of adenoviral-mediated gene transfer of TIMP-1 and -2 in ischemic brain injury

• Published in: Gene therapy Vol. 14; no. 7; pp. 621 - 625
• Main Authors: MAGNONI, S, BAKER, A, THOMSON, S, JORDAN, G, GEORGE, S. J, MCCOLL, B. W, MCCULLOCH, J, HORSBURGH, K
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01-04-2007
• Subjects: Adenoviridae - genetics; Adenovirus; Adenoviruses; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Applied cell therapy and gene therapy; beta-Galactosidase - genetics; Biological and medical sciences; Biotechnology; Blotting, Western - methods; Brain damage; Brain injury; Care and treatment; Cerebral ischemia; Corpus Striatum - chemistry; Corpus Striatum - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene therapy; Genetic aspects; Genetic Therapy - methods; Genetic transformation; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Health aspects; Health. Pharmaceutical industry; Industrial applications and implications. Economical aspects; Inhibitor drugs; Injections; Ischemia; Ischemic Attack, Transient - metabolism; Ischemic Attack, Transient - pathology; Ischemic Attack, Transient - therapy; Male; Matrix metalloproteinase; Medical sciences; Mice; Mice, Inbred C57BL; Neostriatum; Neurology; Neurons - metabolism; Neurons - pathology; Neurons - virology; Neuroprotection; Neurosciences; Physiological aspects; Proteolysis; Rodents; Tissue inhibitor of metalloproteinase 1; Tissue inhibitor of metalloproteinase 2; Tissue Inhibitor of Metalloproteinase-1 - analysis; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Tissue Inhibitor of Metalloproteinase-2 - analysis; Tissue Inhibitor of Metalloproteinase-2 - genetics; Tissue Inhibitor of Metalloproteinase-2 - metabolism; Transduction, Genetic - methods; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Vascular diseases and vascular malformations of the nervous system; United Kingdom; matrix metalloproteinases (MMPs); Adenoviridae; Injury; Cardiovascular disease; adenoviral vector; tissue inhibitors of matrix metalloproteinases (TIMPs); mice; Vascular disease; Tissue; cerebral ischemia; Vector; Cerebrovascular disease; Nervous system diseases; Rodentia; Cerebral disorder; Genetic transfer; Virus; Vertebrata; Mammalia; Mouse; neuroprotection; Central nervous system disease; Brain ischemia; Inhibitor; Gene therapy
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3302894

Gene therapy may be a promising approach for treatment of brain ischemia. We and others previously demonstrated that increased activity of matrix metalloproteinases (MMPs) contributes to the tissue damage that results from ischemic injury. The proteolysis of MMPs is tightly controlled by tissue inhibitors of MMPs (TIMPs). In this study, we examined whether adenoviral-mediated gene transfer of TIMP-1 and TIMP-2 could protect against neuronal damage induced by global cerebral ischemia in mice. An adenovirus expressing TIMP-1 or TIMP-2 (AdTIMP-1 or AdTIMP-2) or a control adenovirus (RAd60) or vehicle was injected into the striatum 3 days before transient global cerebral ischemia. The extent of neuronal damage was quantified 3 days post-ischemia. There was no significant difference in the extent of neuronal damage in vehicle as compared to RAd60-treated mice. In contrast, neuronal damage was reduced, by approximately 50%, after gene transfer of AdTIMP-1 (P<0.001) and AdTIMP-2 (P< 0.01) as compared to controls. This study provides the first in vivo evidence of the protective effects of TIMP-1 and TIMP-2 via gene transfer in global ischemia.