Abstract
Purpose :
Open-angle glaucoma (OAG) is characterized by increased intraocular pressure (IOP) and is a leading cause of vision loss. Prostaglandin analog eye drops are effective at reducing IOP, but patient compliance is extremely poor. Here we evaluate a recombinant adeno-associated virus-mediated (rAAV) gene therapy treatment to permanently lower IOP through the de novo biosynthesis of prostaglandin F2α (PGF2α) following intracameral injection, in the DBA/2J congenital glaucoma mouse.
Methods :
DBA/2J mice (N=20/cohort) were assigned to a natural history (NH, no treatment), sham (S, vehicle only), low dose rAAV (LD; 4.0×109 vg/eye), or high dose rAAV cohort (HD; 4.0×1010 vg/eye). Mice received bilateral 1.5µL intracameral injections at 4-months and underwent tonometry, slit-lamp and pattern electroretinography (pERG) variously at 3, 4, 5, 6, 8, 9 and 10-months. Mice were euthanized and RBPMS staining used to quantify retinal ganglion cells (RGCs) on whole mounts, while optic nerves were processed with toluidine blue to determine damage.
Results :
Slit lamp imaging revealed iris defects and pigment dispersion in all cohorts, as expected of the DBA/2J model. Tonometry at 8-months revealed a significant IOP decrease in LD vs NH cohorts (31.25%; p<0.0001) and HD vs NH cohorts (21.63%; p<0.0001). Similarly, IOP was significantly decreased in LD vs S cohorts (25.97%; p<0.0001) and in HD vs S cohorts (15.61%; p<0.0001) (Two-way ANOVA, Tukey’s post hoc). pERG amplitudes were essentially absent in NH (0.8144µV) and S (0.4924µV) cohorts but preserved in LD (2.531µV) and HD (3.049µV) treated cohorts, reaching statistical significance in NH vs LD (p=0.0309), NH vs HD (p=0.0023), S vs LD (p=0.0074) and S vs HD (p=0.0004) comparisons (one-way ANOVA, Tukey’s post hoc). RBPMS staining show evidence of anatomical RGC preservation in LD and HD treated cohorts; analysis of optic nerve damage is being processed.
Conclusions :
rAAV2/5 mediated de novo biosynthesis of PGF2α from the corneal endothelium following intracameral delivery significantly lowered IOP in DBA/2J mice at 8-10 months. pERG revealed an absence of RGC function in NH/S groups that was corrected in LD/HD groups, indicating functional preservation following a single dose. If successfully translated, this gene therapy would represent a paradigm shift in the clinical management of OAG, allowing long-term IOP reduction without adherence to a daily treatment regimen.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.