Local Administration of an Adeno-associated Viral Vector Expressing IL-10 Reduces Monocyte Infiltration and Subsequent Photoreceptor Damage during Experimental Autoimmune Uveitis

Abstract

Autoimmune posterior uveitis is a chronic, potentially blinding inflammatory disease of the eye. It is commonly treated with immunosuppressive drugs that have adverse long-term effects. Advances in gene transfer techniques have enabled long-term, stable transduction of retinal cells following subretinal injection with adeno-associated viral (AAV) vectors. Here we report for the first time that subretinal injection of rAAV-2 encoding murine IL-10 into the retina of C57BL/6 mice significantly decreases the median experimental autoimmune uveitis (EAU) disease severity. This protection is shown to be due to a decrease in the number and activation status of infiltrating monocytes during EAU, as determined by costimulatory molecule expression and nitrotyrosine detection. No differences within splenocyte proliferative responses or serum antibody levels were detected, emphasizing the potential of gene therapy strategies in ameliorating autoimmune responses in local microenvironments without unwanted systemic effects.

Assessment of ocular transduction using single-stranded and self-complementary recombinant adeno-associated virus serotype 2/8

“…However, genes that might be packaged in sc vectors include genes that encode many small neurotrophic and immunomodulatory factors and siRNA molecules. 28,29 Our findings and other work in the murine 30-32 rat 33,34 and canine retina 35 have shown AAV2-and 2/5-mediated GFP expression to be stronger in the RPE layer relative to the outer nuclear layer (ONL), suggesting that AAV2 and 2/5 have a higher tropism for RPE cells than for photoreceptors. AAV2/8 demonstrates an equal tropism as GFP signal intensity appears similar for the two cell types.…”

Cytokines and Chemokines in Uveitis - Is there a Correlation with Clinical Phenotype?

“…68 More recently, the local administration of an adeno-associated viral vector expressing IL-10 significantly decreased experimental autoimmune uveitis disease severity. 69 It is not clear how IL-10 acts as a suppressor for IFN-γ production in T cells, but in macrophages, it has been demonstrated that IL-10 reduces the stability of mRNA for IL-6. 55…”

Gene therapy progress and prospects: the eye

“…47 rAAV-2-mediated expression of IL-10 significantly decreases disease severity of EAU without affecting splenocyte proliferative responses or serum antibody levels, illustrating the potential of gene therapy strategies to modulate immune responses in local microenvironments without unwanted systemic effects. 48 Expression of CNTF or GDNF by adenoviral and lentiviral vectors prolong retinal ganglion cell survival following axonal injury. 49 rAAV-mediated expression of brain-derived neurotrophic factor (BDNF), enhanced by the incorporation of the woodchuck hepatitis posttranscriptional regulatory element, is of rapid-onset and high efficiency in retinal ganglion cells, leading to significant retinal ganglion cell survival in experimental glaucoma.…”