Abstract
Purpose :
Glaucoma is one of the leading causes of irreversible blindness globally and increased intraocular pressure (IOP) is a major risk factor. We have recently developed a partially open angle mouse model of glaucoma termed the AP-2β trabecular meshwork region knockout (AP-2β TMR KO), where the gene encoding transcription factor AP-2β, tfap2b, is conditionally deleted using MgpCre recombinase. Using this model, we aim to identify alternative approaches for treatment of the disease and determine the impact of long-term treatment on the outflow pathways.
Methods :
AP-2β TMR mutant and wildtype mice were treated with 0.005% latanoprost (LTP), a prostaglandin analogue, once daily. In addition, a mucoadhesive micelle-based polymer system loaded with 0.005% LTP was employed to facilitate effective, longer term drug delivery. Baseline measurements of IOP were taken prior to treatment with subsequent measurements taken at 20 minutes, 1 hour, 24 hours and 5 days post treatment. For the extended treatment groups IOP was taken before treatment and then every 3 days until study completion. Mice were euthanized and eyes were prepared for immunohistochemistry to compare the structure and function of the outflow pathways.
Results :
The baseline IOP measurements of mutant mice were significantly higher than that of the wildtype littermates (P ≤ 0.05 and P ≤ 0.0001, respectively). Once treated with LTP, mutants experienced a significant reduction in IOP 20 minutes post treatment (P ≤ 0.001); however, IOP increased again 1 hour post treatment. Long-term LTP treatment was able to produce a downward pattern in the mutant baseline IOP’s presenting a significant reduction in IOP at 35 days of treatment compared to untreated mutants (P < 0.0001). In contrast, the three-day micelle delivered LTP (M-LTP) treatment showed a consistent reduction in IOP after only 5 days of treatment. Additionally, long-term M-LTP treatment resulted in a reduction in baseline IOP earlier and significantly lower than mice treated with LTP alone.
Conclusions :
These results show that LTP treatment can recover functionality of the unconventional outflow pathway where long-term treatment significantly reduced baseline IOP levels in mutant mice. Furthermore, we showed that the 3-day M-LTP treatment was more effective than the daily LTP treatment. Thus, this drug delivery system may slow down the progression of disease and help to preserve remaining visual function.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.