difluprednate and Glaucoma

To evaluate the risk factors associated with clinically important intraocular pressure (IOP) elevation with topical difluprednate treatment in patients with non-infectious uveitis.. Retrospective cohort study.. Fifty-four eyes of 54 patients with non-infectious uveitis treated with topical difluprednate at the current institution were included. Demographics and clinical characteristics of uveitis patients were collected. The main outcome measure was development of clinically important IOP elevation defined as IOP ≥21 mmHg and an increase of ≥10 mmHg from baseline.. A clinically important IOP elevation was observed in 17 patients (31.5%). The mean time to clinically important IOP elevation was 7.4±4.8 weeks (range 3-19). Statistically significant risk factors for incident clinically important IOP elevation were being a child (adjusted hazard ratio [aHR] 7.85 [95% CI 1.48-41.56], P = .02) and concurrent use of systemic steroids (aHR 5.31 [95% CI 1.18-24.00], P = .03). Patients with concurrent systemic corticosteroids developed clinically important IOP elevation earlier than those without systemic corticosteroid (mean 5.7±3.4 [range 3-14] vs 10.4±5.7 [range 4-19] weeks, P = .05). Incident IOP ≥30 mmHg occurred in 7 patients (13.0%). All patients responded well to the cessation of difluprednate and/or use of topical antiglaucomatous agents and no eyes required glaucoma surgery.. This study demonstrated that clinically important IOP elevation is common in uveitis patients with topical difluprednate treatment. Children and patients with concurrent systemic corticosteroids are at substantial risk of developing clinically important IOP elevation.

Topics: Child; Fluprednisolone; Glaucoma; Glucocorticoids; Humans; Intraocular Pressure; Retrospective Studies; Uveitis

Current treatment of glaucoma relies on administration of daily drops or eye surgery. A gene therapy approach to treat steroid-induced glaucoma would bring a resolution to millions of people worldwide who depend on glucocorticoid therapy for a myriad of inflammatory disorders. Previously, we had characterized a short-term Adh.GRE.MMP1 gene vector for the production of steroid-induced MMP1 in the trabecular meshwork and tested reduction of elevated intraocular pressure (IOP) in a sheep model. Here we conducted a trial transferring the same transgene cassette to a clinically safe vector (scAAV2), and extended the therapeutic outcome to longer periods of times. No evidence of ocular and/or systemic toxicity was observed. Viral genome distributions showed potential reinducible vector DNAs in the trabecular meshwork (0.4 v.g. per cell) and negligible copies in six major internal organs (0.00002-0.005 v.g. per cell). Histological sections confirmed successful transduction of scAAV2.GFP to the trabecular meshwork. Optimization of the sheep steroid-induced hypertensive model revealed that topical ophthalmic drug difluprednate 0.05% (durezol) induced the highest IOP elevation in the shortest time. This is the first efficacy/toxicity study of a feasible gene therapy treatment of steroid-induced hypertension using clinically accepted self-complementary adeno-associated vectors (scAAV) vectors in a large animal model.

Topics: Animals; Dependovirus; Disease Models, Animal; Fluprednisolone; Genetic Therapy; Genetic Vectors; Glaucoma; Glucocorticoids; Humans; Intraocular Pressure; Matrix Metalloproteinase 1; Sheep; Trabecular Meshwork