Long-Term Decrease of Intraocular Pressure in Rats by Viral Delivery of miR-146a

PURPOSE: To evaluate the effects of miR-146a in trabecular meshwork (TM) cells and on intraocular pressure (IOP) in vivo via viral delivery of miR-146a to the anterior chamber of rat eyes. METHODS: Human TM cells were transfected with miR-146 mimic or inhibitor. Some cells from each group were then subjected to cyclic mechanical stress (CMS). Other cells from each group had no force applied. Gene expression was then analyzed by quantitative polymerase chain reaction (qPCR). Replication-deficient adenovirus and lentivirus expressing miR-146a were inoculated into the anterior segment of Brown Norway rat eyes. IOP was monitored by rebound tonometry, visual acuity was evaluated by optokinetic tracking (OKT), and inflammation markers in the anterior segment were examined by slit-lamp, qPCR, and semi-thin sections. RESULTS: miR-146 affected the expression of genes potentially involved in outflow homeostasis at basal levels and under CMS. Both lentiviral and adenoviral vectors expressing miR-146a resulted in sustained decreases in IOP ranging from 2.6 to 4.4 mmHg. Long term follow-up of rats injected with lentiviral vectors showed a sustained effect on IOP of 4.4 ± 2.9 mmHg that lasted until rats were sacrificed more than 8 months later. Eyes showed no signs of inflammation, loss of visual acuity, or other visible abnormalities. CONCLUSIONS: Intracameral delivery of miR-146a can provide a long-term decrease of IOP in rats without signs of inflammation or other visible adverse effects. TRANSITIONAL RELEVANCE: The IOP-lowering effects of miR-146 observed in rats provides a necessary step toward the development of an effective gene therapy for glaucoma in humans.