A small molecule PROTAC for macular degeneration - Abstract Age-related macular degeneration (AMD) and related macular dystrophies (MDs) are leading causes of adult blindness with limited treatment options. AMD/MDs can present in two forms, geographic atrophy/GA (dry form) and choroidal neovascularization/CNV (wet form). There is strong evidence linking sterile inflammation to AMD/MD pathogenesis and two complement pathway inhibitors are already approved by FDA for treating GA in the dry form of AMD. However, due to limited therapeutic impact and adverse effects of complement inhibitors and other approved drugs for both dry AMD and wet AMD, there is a significant need for novel therapies for AMD/MDs. Our recently published data and preliminary studies identified secretory phospholipase A2-IIA (sPLA2-IIA), a pro-inflammatory enzyme, as a key molecular player in AMD/MD pathogenesis. AMD/MD primarily affect the retinal pigment epithelium (RPE) cells in the eye and patient-derived induced pluripotent stem cell- RPE (iRPE) from AMD and 2 distinct MDs showed elevated levels of sPLA2-IIA. Furthermore, AMD/MD iRPE cultures and AMD donor eyes showed elevated sPLA2-IIA levels in drusen, a pathological hallmark of early AMD/MD that is the key driver of later stage pathologies in AMD/MDs. Notably, pharmacological modulation of sPLA2-IIA activity in AMD and MD iRPE cultures led to reduced drusen. In addition, directly linking elevated sPLA2-IIA activity to AMD/MD pathology, sPLA2-IIA overexpression led to AMD-associated pathological alterations (drusen, Bruch’s membrane thickening, RPE thinning, CNV and visual deficits) in C57BL/6J mice. Altogether, these studies provide a strong rationale for targeting sPLA2-IIA activity in AMD/MDs. Toward this goal, we propose to develop proteolysis-targeting chimeras (PROTAC) compounds for specific inhibition of sPLA2-IIA in AMD/MDs. In initial experiments, we have synthesized a ‘lead‘ PROTAC (UR-00059) that can induce degradation of sPLA2-IIA in iRPE cells with half-maximal degradation concentration DC50 of 295.5 nM. The following milestone-driven aims will allow us to develop an effective PROTAC-based therapy targeting sPLA2-IIA for AMD/MDs. Aim 1: Optimize UR-00059 structure and activity and characterize the target engagement in vivo; Aim 2: Conduct in vivo efficacy studies and non-GLP absorption, distribution, metabolism, and toxicology of UR-00059; Aim 3: Perform IND enabling studies and obtain FDA approval for human testing. Ultimately, the proposed studies will develop a novel PROTAC-based therapy for targeting inflammation, drusen and consequently late stage pathologies of AMD and related MDs.
