Abstract
Purpose :
Vutiglabridin is an orally administered clinical phase II-stage small molecule for treating obesity. It modulates paraoxonase-2 (PON2), a novel mitochondrial protein that enhances lipid metabolism and mitochondrial function via autophagy activation. Currently, dysfunctions of the above biological activities in retinal pigment epithelium (RPE) have been proposed as causes of age-related macular degeneration (AMD). PON2 is highly expressed in RPE. Therefore, we hypothesized that vutiglabridin may also attenuate neovascular AMD (nAMD) via PON2, as a novel mechanism of action.
Methods :
Ocular pharmacokinetics was performed in RPE of C57BL/6 mice by LC-MS/MS analysis at 0, 1, 2, 4, 6, 8, 10, 24 hours after oral gavage of vutiglabridin. To induce choroidal neovascularization (CNV), 8-week-old C57BL/6 mice (wildtype or PON2-/-) were irradiated with laser (250 mW, 0.1 s, 50 μm spot) and then vutiglabridin was daily administered via oral gavage for 6 days. Aflibercept (2 µg/µl) was intravitreally injected immediately after surgery, as positive comparator or as combinatorial drug. Retinal function (electroretinogram (ERG)), CNV volume, and RPE mitochondrial function (MitoSOX and OCR) were evaluated. Retinal tissues were analyzed for VEGF, HIF-1α, HO-1, IL-1α, IL-1β, and IL-6 level.
Results :
Oral administration of vutiglabridin led to 1:1 ratio of concentration between plasma and RPE in mice, confirming target tissue engagement at its clinical dose. Vutiglabridin significantly improved ERG and reduced CNV volume (70.5±9.7%) in a manner comparable to aflibercept (59.7±9.3%). Vutiglabridin also improved mitochondrial function in isolated RPE tissues and reduced all assayed markers of nAMD in retinal tissues similar to aflibercept. These effects were abrogated in PON2-/- mouse, thus validating its target as PON2. When administered in combination with aflibercept, vutiglabridin further reduced CNV lesion volume by 52.5±13.7%.
Conclusions :
Vutiglabridin is as potent as aflibercept in laser-induced CNV mouse model through a novel mechanism of PON2 modulation that is complementary to VEGF inhibition. These results support and call for further evaluations of PON2 as a novel target and the immediate clinical development of vutiglabridin as mono- or combinatorial therapy for the treatment of nAMD.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.