Development of a novel therapy for the treatment of age-related macular degeneration

项目总结 老年性黄斑变性(AMD)是导致失明的主要原因之一，在美国有1800万人受到影响。这个 湿性AMD以病理性新生血管和黄斑出血为特征，而干性AMD以病理性新生血管和黄斑出血为特征 形态的特点是没有可见的血管形成。治疗湿性AMD的策略，包括抗氧化治疗， 预防性激光治疗、手术干预和抗新生血管药物主要是姑息性和延伸性的。 病人保持功能性视力的时间。目前所有FDA批准的AMD治疗方法都侧重于延缓 通过抑制血管内皮细胞生长因子(VEGF)途径而导致疾病湿润期的进展。 然而，湿性AMD是在干性AMD的背景下形成的，而干性AMD总是在新生血管形成之前发展。这个 目前干性AMD的护理标准通过以下方式降低了从中级到晚期AMD的进展风险 ~25%，但不能预防AMD的发病。没有FDA批准的治疗干性AMD的药物治疗。的一个标志 AMD是在视网膜色素上皮(RPE)细胞的溶酶体中积聚的双维甲酸。最多的 常见的双维A酸类化合物，N-视黄基-N-视黄醇乙醇胺(A2E)是视觉周期的副产品。 A2E在细胞培养模型中具有细胞毒性，似乎是脂褐素形成的原因之一。 脂褐素双维A酸类化合物是强健的，通常不会被溶酶体酶降解。随着时间的推移，它们会积累起来 并与溶酶体功能障碍和AMD的进展有关。分解积累的策略 脂褐素有可能延缓甚至逆转干性AMD。Ichor Treateutics正在开发一种新型酶 我们打算将其作为FDA批准的第一种干性AMD药物推向市场。基于我们的突破 在体外和AMD小鼠模型中发现重组锰过氧化物酶降解A2E，我们 正在扩大这项工作，以确定适合临床开发的过氧化物酶。主要特征是高 溶酶体pH下的活性，A2E和相关维甲酸降解能力的增加，服从于 细胞和溶酶体输送工程，适用于细菌系统的大规模生产。这个 我们第一阶段的工作范围包括：1)从不同微生物中产生和鉴定过氧化物酶 来源，2)将最佳执行的过氧化物酶与细胞穿透肽偶联以优化靶向 RPE细胞和亚细胞靶向溶酶体，以及3)评估眼部耐受性和生物活性。 AMD动物模型的建立。成功完成我们的目标将证明对我们的领先地位的支持研究是正确的 酶在第二阶段。

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.