Uveoretinitis is an ocular autoimmune disease caused by the activation of autoreactive T- cells targeting retinal antigens. The myxoma M013 gene is known to block NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells) and inflammasome activation, and its gene delivery has been demonstrated to protect the retina against lipopolysaccharide (LPS)-induced uveitis. In this report we tested the efficacy of M013 in an experimental autoimmune uveoretinitis (EAU) mouse model. B10RIII mice were injected intravitreally with AAV (adeno associated virus) vectors delivering either secreted GFP (sGFP) or sGFP-TatM013. Mice were immunized with interphotorecptor retinoid binding protein residues 161–180 (IRBP161–180) peptide in complete Freund’s adjuvant a month later. Mice were evaluated by fundoscopy and spectral domain optical coherence tomography (SD-OCT) at 14 days post immunization. Eyes were evaluated by histology and retina gene expression changes were measured by reverse transcribed quantitative PCR (RT-qPCR). No significant difference in ERG or retina layer thickness was observed between sGFP and sGFP-TatM013 treated non-uveitic mice, indicating safety of the vector. In EAU mice, expression of sGFP-TatM013 strongly lowered the clinical score and number of infiltrative cells within the vitreous humor when compared to sGFP treated eyes. Retina structure was protected, and pro-inflammatory genes expression was significantly decreased. These results indicate that gene delivery of myxoma M013 could be of clinical benefit against autoimmune diseases.
The advanced form of AMD, geographic atrophy, is associated with increased RPE oxidative stress and chronic inflammation. Here we evaluated the effects of delivering an anti-inflammatory viral gene by an AAV-vector in a mouse model of geographic atrophy. We measured changes in retinal function, structure, and morphology over nine months with electroretinography, optical coherence tomography, and fundoscopy, respectively. In addition, we used retinal tissue to quantify changes in markers of inflammation by multiplex ELISA, RT-qPCR, and immunofluorescence staining. Our AAV significantly delayed the loss of retinal function and structure and decreased retinal inflammation compared to the control AAV treatment. Our results suggest that modulating retinal inflammation could significantly slow the progression of geographic atrophy.
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