期刊
HUMAN GENE THERAPY
卷 26, 期 1, 页码 59-68出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/hum.2014.089
关键词
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资金
- National Eye Institute [R01 EY02025]
- Florida Biomedical Research Foundation [e-10KG-s]
- Macula Vision Research Foundation
- NEI [P30 EY02172]
- NIAID [R01 AI100987]
- NATIONAL EYE INSTITUTE [R24EY022023, R01EY024280, P30EY021721] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI100987] Funding Source: NIH RePORTER
Inflammation of the retina is a contributing factor in ocular diseases such as uveitis, diabetic retinopathy, and age-related macular degeneration (AMD). The M013 immunomodulatory protein from myxoma virus has been shown to interfere with the proinflammatory signaling pathways involving both the NLRP3 inflammasome and NF-kappa B. We have developed and characterized an adeno-associated viral (AAV) vector that delivers a secretable and cell-penetrating form of the M013 protein (TatM013). The expressed TatM013 protein was secreted and blocked the endotoxin-induced secretion of interleukin (IL)-1 beta in monocyte-derived cells and the reactive aldehyde-induced secretion of IL-1 beta in retinal pigment epithelium cells. The local anti-inflammatory effects of AAV-delivered TatM013 were evaluated in an endotoxin-induced uveitis (EIU) mouse model after intravitreal injection of mice with an AAV2-based vector carrying either TatM013 fused to a secreted green fluorescent protein (GFP) tag (sGFP-TatM013) or GFP. Expression of the sGFP-TatM013 transgene was demonstrated by fluorescence funduscopy in living mice. In EIU, the number of infiltrating cells and the concentration of IL-1 beta in the vitreous body were significantly lower in the eyes injected with AAV-sGFP-TatM013 compared with the eyes injected with control AAV-GFP. These results suggest that a virus-derived inhibitor of the innate immune response, when delivered via AAV, could be a generalized therapy for various inflammatory diseases of the eye.
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