Investigating the role of PLA2G2A/sPLA2-IIA in macular degeneration - Abstract Age-related macular degeneration (AMD) is a leading cause of adult blindness with limited treatment options. AMD can present in two forms: geographic atrophy (dry form) and choroidal neovascularization/ CNV (wet form). Strong evidence links sterile inflammation to AMD pathogenesis, and the FDA has already approved two complement pathway inhibitors for treating geographic atrophy (dry form). However, due to the limited therapeutic impact and adverse effects of complement inhibitors and other approved drugs for both dry AMD and wet AMD, there is an urgent need to identify novel therapeutic targets for AMD. Our recently published data and preliminary studies identified secretory phospholipase A2-IIA (PLA2G2A/sPLA2-IIA), a pro-inflammatory enzyme, as a key molecular player in AMD pathogenesis. AMD primarily affects the retinal pigment epithelium (RPE) cells, with drusen underlying RPE cells as an early pathological biomarker of the disease. AMD iRPE cultures and AMD donor eyes showed elevated PLA2G2A levels in drusen. Furthermore, pharmacological modulation of PLA2G2A in AMD iRPE cultures reduced drusen. In addition, in a proof-of-concept experiment, PLA2G2A overexpression led to AMD-associated pathological alterations (drusen, Bruch's membrane thickening, CNV, and visual deficits) in aged C57BL/6J mice. Altogether, these studies provide strong evidence for a mutation-independent pathogenic role of PLA2G2A in AMD. To critically evaluate the role of PLA2G2A in AMD, in this proposal, we will utilize human donor eyes (Aim 1), and both in vitro (patient-iPSCs) (Aim 2) and in vivo (transgenic mice) approaches (Aim 3). Ultimately, the proposed research has the potential to i) increase our understanding of AMD pathobiology, ii) provide a relevant mouse model of AMD, and iii) yield a novel and mutation-independent therapeutic target for AMD and potentially related macular dystrophies.
