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" AMDform 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 extendthe time a patient retains functional vision. All current FDA-approved AMD treatments focus on slowing theprogression 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. Thecurrent 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 ofAMD is the accumulation of bisretinoids in the lysosomes of retinal pigment epithelium (RPE) cells. The mostcommon 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 upand contribute to lysosomal dysfunction and progression of AMD. Strategies to break down accumulatedlipofuscin have the potential to delay or even reverse dry AMD. Ichor Therapeutics is developing a novel enzymetherapy, which we intend to bring to market as the first FDA-approved dry AMD drug. Based on our breakthroughdiscovery that recombinant manganese peroxidase degrades A2E in vitro and in a mouse model of AMD, weare expanding this work to identify peroxidases suitable for clinical development. Key characteristics are highactivity at lysosomal pH, increased potency for degradation of A2E and related retinoids, amenable toengineering for cell and lysosomal delivery, and suitable for large scale production in bacterial systems. Thescope of our Phase I effort includes: 1) generating and characterizing peroxidases from different microbialsources, 2) conjugating optimally performing peroxidases to cell penetrating peptides to optimize targeting toRPE cells and subcellular targeting to lysosomes, and 3) evaluating ocular tolerance and biological activity in ananimal model of AMD. Successful completion of our objectives will justify IND-enabling studies of our leadenzyme in Phase II.
Public Health Relevance Statement: PROJECT NARRATIVE
Current treatments for age-related macular degeneration (AMD) address the "wet" (characterized by
neovascularization and macular bleeding) form of the disease; there are no approved treatments for the "dry"
(no visible vascularization) form. A hallmark of dry AMD is the accumulation of bisretinoids in the lysosomes of
the retinal pigment epithelium (RPE) cells, inhibition of proteolytic processes, generation of reactive oxygen
species, and impairment of autophagy. We are developing an innovative approach to remove bisretinoids using
peroxidases as a first-in-class treatment for dry AMD.
Project Terms: <2-Aminoethanol> | | | | | | 