PROJECT SUMMARY Age-related macular degeneration (AMD), a leading cause of blindness, affects 18 million people in the US. The “wet” form of AMD is characterized by pathological neovascularization and macular bleeding while the “dry” AMD form is characterized by no visible vascularization. Strategies to treat wet AMD, including antioxidant therapy, prophylactic laser therapy, surgical intervention, and anti-neovascular agents, are primarily palliative and extend the time a patient retains functional vision. All current FDA-approved AMD treatments focus on slowing the progression of the wet stage of the disease by inhibiting the vascular endothelial growth factor (VEGF) pathway. However, wet AMD forms on a background of dry AMD, which always develops before neovascularization. The current standard of care for dry AMD reduces the risk of progression from intermediate to advanced AMD by ~25% but does not prevent onset of AMD. No FDA-approved drug treatments exist for dry AMD. A hallmark of AMD is the accumulation of bisretinoids in the lysosomes of retinal pigment epithelium (RPE) cells. The most common bisretinoid, N-retinyl-N-retinylidene ethanolamine (A2E), develops as a byproduct of the visual cycle. A2E is cytotoxic in cell culture models and appears to be a causative factor in the formation of lipofuscin. Lipofuscin bisretinoids are robust and generally not degraded by lysosomal enzymes. Over time, they build up and contribute to lysosomal dysfunction and progression of AMD. Strategies to break down accumulated lipofuscin have the potential to delay or even reverse dry AMD. Ichor Therapeutics is developing a novel enzyme therapy, which we intend to bring to market as the first FDA-approved dry AMD drug. Based on our breakthrough discovery that recombinant manganese peroxidase degrades A2E in vitro and in a mouse model of AMD, we are expanding this work to identify peroxidases suitable for clinical development. Key characteristics are high activity at lysosomal pH, increased potency for degradation of A2E and related retinoids, amenable to engineering for cell and lysosomal delivery, and suitable for large scale production in bacterial systems. The scope of our Phase I effort includes: 1) generating and characterizing peroxidases from different microbial sources, 2) conjugating optimally performing peroxidases to cell penetrating peptides to optimize targeting to RPE cells and subcellular targeting to lysosomes, and 3) evaluating ocular tolerance and biological activity in an animal model of AMD. Successful completion of our objectives will justify IND-enabling studies of our lead enzyme in Phase II.