Prostaglandin pathway gene therapy for sustained reduction of intraocular pressure.
Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme in prostaglandin (PG) biosynthesis. In the eye, loss of COX-2 expression in aqueous humor-secreting cells has been associated with primary open-angle glaucoma (POAG). Reduction of intraocular pressure (IOP) is the main treatment goal in this disease. We used lentiviral vectors to stably express COX-2 and other PG biosynthesis and response transgenes in the ciliary body epithelium and trabecular meshwork (TM), the ocular suborgans that produce aqueous humor and regulate its outflow, respectively. We show that robust ectopic COX-2 expression and PG production require COX-2 complementary DNA (cDNA) sequence optimization. When COX-2 expression was coupled with a similarly optimized synthetic PGF2alpha receptor transgene to enable downstream signaling, gene therapy produced substantial and sustained reductions in IOP in a large animal model, the domestic cat. This study provides the first gene therapy for correcting the main cause of glaucoma.
Barraza
Román A
RA
Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
McLaren
Jay W
JW
Poeschla
Eric M
EM
D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D002415:Cats; D002924:Ciliary Body / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005901:Glaucoma / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D007429:Intraocular Pressure; D016086:Lentivirus / Q000235:genetics; D008957:Models, Genetic; D011453:Prostaglandins / Q000378:metabolism*; D014129:Trabecular Meshwork / Q000378:metabolism; D019076:Transgenes
D011453:Prostaglandins; D051546:Cyclooxygenase 2