Department of Chemistry, International Institute for Nanotechnology, Northwestern University, Evanston, IL, USA.
Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Sci Adv. 2023 Oct 13;9(41):eadi8534. doi: 10.1126/sciadv.adi8534.
Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in the developed world. Current therapy includes monthly intraocular injections of anti-VEGF antibodies, which are ineffective in up to one third of patients. Thrombospondin-1 (TSP1) inhibits angiogenesis via CD36 binding, and its down-regulated expression is negatively associated with the onset of nAMD. Here, we describe TSP1 mimetic protein-like polymers (TSP1 PLPs). TSP1 PLPs bind CD36 with high affinity, resist degradation, show prolonged intraocular half-lives (13.1 hours), have no toxicity at relevant concentrations in vivo (40 μM), and are more efficacious in ex vivo choroidal sprouting assays compared to the peptide sequence and Eylea (aflibercept), the current standard of care anti-VEGF treatment. Furthermore, PLPs exhibit superior in vivo efficacy in a mouse model for nAMD compared to control PLPs consisting of scrambled peptide sequences, using fluorescein angiography and immunofluorescence. Since TSP-1 inhibits angiogenesis by VEGF-dependent and independent mechanisms, TSP1 PLPs are a potential therapeutic for patients with anti-VEGF treatment-resistant nAMD.
新生血管性年龄相关性黄斑变性（nAMD）是发达国家致盲的主要原因。目前的治疗方法包括每月向眼内注射抗 VEGF 抗体，但多达三分之一的患者对此治疗无效。血小板反应蛋白 1（TSP1）通过与 CD36 结合来抑制血管生成，其表达下调与 nAMD 的发生呈负相关。在这里，我们描述了 TSP1 模拟蛋白样聚合物（TSP1 PLPs）。TSP1 PLPs 与 CD36 具有高亲和力结合，不易降解，在体内具有较长的眼内半衰期（13.1 小时），在相关浓度下（40 μM）无毒性，并且在体外脉络膜发芽试验中比肽序列和 Eylea（阿柏西普）更有效，Eylea 是目前抗 VEGF 治疗的标准治疗方法。此外，与由乱序肽序列组成的对照 PLPs 相比，PLPs 在 nAMD 小鼠模型中表现出更好的体内疗效，通过荧光素血管造影和免疫荧光进行评估。由于 TSP-1 通过 VEGF 依赖和非依赖机制抑制血管生成，因此 TSP1 PLPs 可能是治疗抗 VEGF 治疗耐药性 nAMD 的一种潜在疗法。
