Evaluation of Therapeutic Interventions for the Treatment of Eye Disorders
thesisposted on 2017-10-27, 00:00 authored by Joseph D Bogaard
Purpose The purpose of this thesis work was to evaluate therapeutic interventions for the treatment of various eye disorders using preclinical and clinical studies. The prevention and treatment of postoperative inflammation and fibrosis after pediatric cataract surgery was investigated using a rabbit animal model. The timing of amblyopia therapy following pediatric ocular trauma was examined to determine if a delay in treatment had an effect on visual outcomes. Finally, lead optimization and efficacy studies were performed for a new therapeutic agent for retinal degenerations such as retinitis pigmentosa based on identification of sulfaphenazole from a cellular high throughput screen. Methods Biochemical, cellular, animal, and retrospective human studies were performed to evaluate the effectiveness of different drugs and treatment strategies. Rabbits were used as a model for clear cornea lensectomy procedures to evaluate enoxaparin, triamcinolone, and tissue plasminogen activator. A retrospective examination of all the pediatric cases of ocular trauma that were seen in UIC’s EEI for over 13 years were used to evaluate if the timing of amblyopia therapy affects visual outcomes. Biochemical studies of CYP inhibition, cell death studies with 661W and a mouse model of retinal degeneration were used to evaluate a candidate therapy and its analogs. Results Rabbit studies demonstrated a significant treatment benefit to both enoxaparin, a low molecular weight heparin, for the prevention fibrosis. The effect was augmented by enoxaparin in combination with a low dose intraocular steroid, preservative-free triamcinolone, with a reduction of multiple measures of inflammation and fibrosis. Tissue plasminogen activator was found to be an effective treatment to solubilize fibrin formed in the anterior chamber after lensectomy. In children under the age of 8 with a history of ocular trauma, visual acuity outcomes were improved if amblyopia therapy was initiated within the first three months after the initial injury. Despite promising results in the cell-based studies, our top sulfaphenazole analog, KB-2-001, showed no protection in animal studies. Conclusions There are several promising therapeutic strategies that may have clinical applicability in humans. In particular, preventing and treating children with a history of cataract in need of surgery or a history of ocular trauma demonstrated a significant efficacy that warrants further investigation with the potential to move forward to clinical trials. The prevention and treatment for inherited retinal diseases investigated of inherited retinal degenerations needs further studies before determining its potential therapeutic value.