Prostaglandin-based rAAV-mediated glaucoma gene therapy in Brown Norway rats

• Published in: Communications biology Vol. 5; no. 1; pp. 1169 - 14
• Main Authors: Chern, Kristina J, Nettesheim, Emily R, Reid, Christopher A, Li, Nathan W, Marcoe, Gavin J, Lipinski, Daniel M
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 03.11.2022; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Anterior chamber; Atrophy; Biology; Electrophysiology; Gene therapy; Genetic Therapy; Glaucoma; Glaucoma - genetics; Glaucoma - therapy; Glaucoma, Open-Angle - drug therapy; Ocular Hypertension - drug therapy; Optic nerve; Pressure; Prostaglandin F2a; Prostaglandins - therapeutic use; Rats; Rodents; Norway
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-022-04134-w

Prostaglandin analogs are first-line treatments for open angle glaucoma and while effective at lowering intraocular pressure, they are undermined by patient non-compliance, causing atrophy of the optic nerve and severe visual impairment. Herein, we evaluate the safety and efficacy of a recombinant adeno-associated viral vector-mediated gene therapy aimed at permanently lowering intraocular pressure through de novo biosynthesis of prostaglandin F2α within the anterior chamber. This study demonstrated a dose dependent reduction in intraocular pressure in normotensive Brown Norway rats maintained over 12-months. Crucially, therapy could be temporarily halted through off-type riboswitch activation, reverting intraocular pressure to normal. Longitudinal multimodal imaging, electrophysiology, and post-mortem histology revealed the therapy was well tolerated at low and medium doses, with no major adverse effects to anterior chamber health, offering a promising alternative to current treatment strategies leading to clinically relevant reductions in intraocular pressure without the need for adherence to a daily treatment regimen.