Adenoviral reporter gene transfer to the human trabecular meshwork does not alter aqueous humor outflow. Relevance for potential gene therapy of glaucoma

Obstruction of the aqueous humor outflow from the anterior chambers of the eye leads to an elevation of intraocular pressure in glaucoma, the second m ajor cause of blindness world-wide. Our goal is to be able to modulate aque ous humor outflow resistance by gene transfer to the cells of the trabecula r meshwork (TM). We have previously shown that adenoviral vectors are able to transfer a reporter gene to the TIW of post-mortem human donors. However , assessing gene therapy for glaucoma requires models that can monitor chan ges in aqueous humor outflow facility (C=flow/pressure). In this study we u sed four replication-deficient adenoviruses in two such perfusion models. I n the first model, whole porcine eyes were infected, perfused at constant p ressure and flow changes recorded for 5 h. In the second one, anterior segm ents from human eyes were infected, perfused at constant flow and pressure changes recorded for 3 days. A single dose of 10(8) adenovirus plague formi ng units (pfu) causes a reduction in C while single doses of 10(7), 10(6) a nd 10(5) p.f.u. do not affect outflow facility and retain positive gene tra nsfer. These findings indicate that adenovirus, at effective doses, could b ecome useful vectors for gene therapy of glaucoma.