Abstract
Purpose :
Overexpression of histone deacetylase (HDAC) and protein misfolding are implicated in many ophthalmic disorders including corneal scar formation, glaucoma, choroidal neovascularization (CNV) and retinal neurodegeneration. While currently available treatment options have improved the visual outcome, they are far from achieving a 100% success rate (non-responsiveness between 8 and 50% in CNV). An HDAC inhibitor as an alternative treatment option would be helpful as an independent treatment or adjunct to existing therapies. The purpose of our study was to test the safety and corneal adherence of novel version of a potent endogenous HDAC inhibitor: butyric acid (BA).
Methods :
A co-polymer based, amphiphilic, self-assembling prodrug-nanoparticles of butyric acid (BNPs) were prepared. BNPs of size 40-50 nm were shown to release BA over 24-48 hrs. in serum. We tested the topical application (15.6 mg/mL) of TAMRA-labeled BNPs in wild type mice. A group of adult C57BL/6 mice (n=6) were dosed once a day for 3 days with TAMRA-labeled BNPs as a 10 μL eyedrop in one eye and the equivalent volume of PBS in the other eye as a control. Photographs of the cornea were taken before and at 3 hours after the last dose. After that, eyes were enucleated, cryopreserved and cryosectioned. Fluorescent imaging and histological evaluation of eyes was performed.
Results :
All mice had clear and healthy-looking corneas at the beginning of the test and photographs showed no signs of inflammation or irritation. At the end of the dosing the ocular media were fully transparent, and the fundus had normal appearance in all mice. Histological evaluation showed no changes in the structure of the eye as a result of the dosing, incl. the retina and RPE. Clear fluorescence signal from TAMRA (at 579 nm) was detected 3 hours after the last dose on the corneal surface.
Conclusions :
Topical administration of BNPs was found to be safe for ocular tissues in wild type mice after short-term dosing. BNPs appear to adhere to the corneal surface even after 3 hours of last application, which shows a potential for treatment of various anterior segment eye diseases. Research is ongoing to validate the efficacy of the proposed therapeutic agent.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.