Biodegradable serpin-peptide-carrying nano- and microparticles for wet AMD

描述(申请人提供)：湿性老年性黄斑变性(AMD)是美国60岁以上患者严重视力丧失和失明的最常见原因。视网膜下新生血管是导致最严重的视力丧失的原因。一种新发现的多肽SP6001有望用于治疗湿性AMD，因为它通过多种抗血管生成机制发挥作用。小肽作为治疗药物具有许多优点，如高特异性和低毒性，但它们的主要缺点是 半衰期很短。为了克服这一可能的限制，将构建一种新的逆转录版本的多肽，并通过将其包裹在聚合物颗粒系统中来保护其免受降解。微粒递送系统将确保安全有效地递送新型抗血管生成多肽及其在眼睛内的受控释放。将合成新的生物材料和颗粒配方，然后对颗粒性质、多肽释放和体外生物活性进行评价。在对人视网膜内皮细胞进行实验后，颗粒/肽系统将在湿性AMD小鼠模型中进行活体测试。逆转肽将与标准肽和搅拌肽进行比较，颗粒制剂的疗效将进行4个月的评估。此外，还将进行体外测试，以确定该肽作用于哪些受体，以及在正常情况下和AMD条件下这些受体在眼睛中的分布情况。一种新的有效的治疗模式可以同时抑制血管内皮生长因子介导的和非血管内皮生长因子介导的血管生成途径，并且可以减少必要的玻璃体内注射的频率，这将显著改善目前使用的AMD治疗方法。

DESCRIPTION (provided by applicant): Wet age-related macular degeneration (AMD) is the most prevalent cause of severe vision loss and blindness in patients over the age of 60 in the US. Subretinal neovascularization is responsible for most severe loss of vision. A newly discovered peptide, SP6001, is promising for treating wet AMD as it works through multiple antiangiogenic mechanisms. Small peptides possess many advantageous characteristics as therapeutic agents, such as high specificity and low toxicity, but their main disadvantage is their short half-life. To counter this possible limitation, a novel retroinverted version of the peptide ill be constructed and it will be protected from degradation by being encapsulated within a polymeric particle system. The particle delivery systems will ensure safe and effective delivery of the novel antiangiogenic peptide along with its controlled release within the eye. New biomaterials and particle formulations will be synthesized and then particle properties, peptide release, and biological activity in vitro evaluated. Following experiments on human retinal endothelial cells, the particle/peptide systems will be tested in vivo in mouse models for wet AMD. Retroinverted peptide will be compared to standard and scrambled peptide and efficacy of particle formulations will be evaluated for 4 months. In vitro assays will also be performed to identify the receptors that the peptide acts on and the distribution of these receptors in the eye under normal conditions and under AMD conditions. A new validated treatment modality that can inhibit both VEGF-mediated and non-VEGF- mediated angiogenic pathways and that can reduce the frequency of necessary intravitreal injections would significantly improve the currently used treatments for AMD.