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

项目摘要 视网膜相关性黄斑变性（AMD）是导致失明的主要原因，在美国影响着1800万人。的 “湿性”AMD的特征在于病理性新生血管形成和黄斑出血，而“干性”AMD的特征在于病理性新生血管形成和黄斑出血。 形式的特征在于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的， 患者保持功能性视力的时间。目前所有FDA批准的AMD治疗方法都侧重于减缓 通过抑制血管内皮生长因子（VEGF）途径来抑制疾病的湿性阶段的进展。 然而，湿性AMD是在干性AMD的背景下形成的，干性AMD总是在新血管形成之前发展。的 目前治疗干性AMD的标准通过以下方式降低了从中度AMD进展到晚期AMD的风险 约25%，但不能预防AMD的发作。没有FDA批准的药物治疗干性AMD。的标志 AMD是双类视色素在视网膜色素上皮（RPE）细胞的溶酶体中的积累。最 常见的双视黄酸，N-视黄基-N-亚视黄基乙醇胺（A2 E），作为视觉循环的副产物产生。 A2 E在细胞培养模型中具有细胞毒性，似乎是脂褐素形成的致病因子。 脂褐素双视黄酸是稳健的，并且通常不被溶酶体酶降解。随着时间的推移，它们逐渐累积 并导致溶酶体功能障碍和AMD的进展。分解积累的战略 脂褐素具有延迟甚至逆转干性AMD的潜力。Ichor Therapeutics正在开发一种新的酶 我们打算将其作为第一个FDA批准的干性AMD药物推向市场。基于我们的突破 发现重组锰过氧化物酶在体外和AMD小鼠模型中降解A2 E，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。关键特征高 在溶酶体pH下的活性，A2 E和相关类维生素A降解的效力增加，适合于 用于细胞和溶酶体递送的工程化，并且适合于在细菌系统中的大规模生产。的 我们第一阶段的工作范围包括：1）从不同的微生物中产生和表征过氧化物酶 2）将最佳性能的过氧化物酶与细胞穿透肽缀合以优化靶向， RPE细胞和亚细胞靶向溶酶体，和3）评估眼耐受性和生物活性， AMD动物模型。成功完成我们的目标将证明对我们的铅进行IND使能研究是合理的 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.