335. Long-Term Genetic Modification of the Ocular Outflow Tract Coupled with Non-Invasive Real-Time Imaging of Gene Expression

Abstract

Top of pageAbstract The anterior chamber of the human eye is the site of dysregulated outflow of aqueous humor that underlies the intraocular hypertensive pathophysiology of glaucoma, a chronic disease that remains one of the leading causes of irreversible blindness worldwide. We hypothesized that the distinctive properties of this circulation could enable a unique approach to problems of accessibility and scale that have hindered the realization of gene therapy and monitoring of its efficacy. Permanent, properly targeted transgene expression within the anterior chamber would facilitate glaucoma research and development of glaucoma gene therapy, but this has not been achieved. In this study with 19 domestic cats, a model chosen for a larger, available animal with similarity to the human eye, we show reproducible high grade, stable transgenesis of the entire critical target tissue, the trabecular meshwork, with lentiviral vectors. The virtually complete transduction is targeted to this tissue within the anterior chamber, occurs after a single trans-corneal injection and persists stably for more than 10 months. It can be monitored serially and non-invasively in living animals. These studies provide a basis for administering glaucoma gene therapy to the anterior chamber of the eye and development of new glaucoma disease models.