A small molecule protac for macular degeneration

The National Eye Institute awarded the University of Rochester a $2,215,463 cooperative agreement on March 17, 2026, under the Vision Research program (CFDA 93.867) to develop small molecule PROTAC compounds targeting secretory phospholipase A2-IIA (SPLA2-IIA) for treatment of age-related macular degeneration and related macular dystrophies.

The award funds development of proteolysis-targeting chimera compounds designed to induce degradation of SPLA2-IIA, a pro-inflammatory enzyme identified as a key driver of macular pathology. Preliminary studies by the recipient linked elevated SPLA2-IIA activity to drusen formation, retinal pigment epithelium dysfunction, and visual deficits in animal models and patient-derived induced pluripotent stem cell cultures. The recipient has already synthesized a lead PROTAC candidate (UR-00059) capable of inducing SPLA2-IIA degradation. This therapeutic approach addresses a significant gap in AMD/macular dystrophy treatment, as existing complement pathway inhibitors approved for geographic atrophy (dry AMD) show limited efficacy and adverse effects across both dry and wet forms of the disease.

Work is performed in Rochester, New York, with a period of performance through February 28, 2027. The Vision Research program supports innovative research to understand the eye and visual system, prevent and treat vision diseases, and expand opportunities for people who are blind or require vision rehabilitation.

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.