Prevention of experimental autoimmune uveitis by intravitreal AAV-EqIL-10

Abstract

Purpose : Non-infectious uveitis (NIU) is an intractable and painful disease that is a significant cause of vision loss in humans and horses. Current treatments of NIU are non-specific and have serious side effects which limits them to short-term use. As NIU necessitates long-term immunosuppression to prevent vision loss, a single dose treatment that mediates long-term immunosuppression without side effects is desired. The purpose of this work was to develop an effective long-term therapy for NIU in horses. We investigated the use of adeno-associated virus (AAV) gene therapy as a vehicle for delivering anti-inflammatories to the uveal tract. The ciliary body was the targeted ocular tissue for gene therapy as it is the location of the blood ocular barrier break down. We exploited the use of an endogenous anti-inflammatory protein, Equine-IL10.

Methods : To simulate the prevention of NIU, naïve Lewis rats received a single intravitreal injection of a low dose or high dose AAV particles harboring codon-optimized cDNAs encoding Equine-IL10 one week prior to experimental autoimmune uveitis (EAU) induction. Daily blinded biomicroscopy examination and optical coherence tomography (OCT) examinations were performed. Genome biodistribution and transduction efficiency were characterized using Q-PCR for ocular tissues. Blinded histological examinations were performed and the level of inflammation was scored. To determine if intravitreal injection of AAV vectors resulted in an antibody response to the injected capsid, neutralizing antibody assays were performed.

Results : Intravitreal injection of AAV-EqIL-10 successfully mediated expression of Equine-IL-10 in the ciliary body of both treatment groups. There was a dose dependent influence of viral expression in other ocular tissues. There was a significant decrease in clinical and histological inflammatory scores in both treatment groups compared to control EAU eyes (p<0.5). Mean cellular infiltrative scores were significantly less in treated eyes compared to control eyes on days 10, 12 and 14 post EAU induction (p<0.5).

Conclusions : Localized gene delivery of Equine-IL10 establishes a long-term anti-inflammatory effect, that would be a novel therapeutic strategy for refractory and recurrent uveitis as well as other ocular autoimmune inflammatory diseases in both human and veterinary patients.

This is a 2021 ARVO Annual Meeting abstract.