Vascular normalizing strategies, aimed at ameliorating blood vessel perfusion and lessening tissue hypoxia, are treatments that may improve the outcome of cancer patients. Secreted class 3 semaphorins (SEMA3), which are thought to directly bind neuropilin (NRP) co-receptors that, in turn, associate with and elicit plexin (PLXN) receptor signaling, are effective normalizing agents of the cancer vasculature. Yet, SEMA3A was also reported to trigger adverse side effects via NRP1. We rationally designed and generated a safe, parenterally deliverable, and NRP1-independent SEMA3A point mutant isoform that, unlike its wild-type counterpart, binds PLXNA4 with nanomolar affinity and has much greater biochemical and biological activities in cultured endothelial cells. In vivo, when parenterally administered in mouse models of pancreatic cancer, the NRP1-independent SEMA3A point mutant successfully normalized the vasculature, inhibited tumor growth, curbed metastatic dissemination, and effectively improved the supply and anticancer activity of chemotherapy. Mutant SEMA3A also inhibited retinal neovascularization in a mouse model of age-related macular degeneration. In summary, mutant SEMA3A is a vascular normalizing agent that can be exploited to treat cancer and, potentially, other diseases characterized by pathological angiogenesis.

旨在改善血管灌注和减轻组织缺氧的血管正常化策略是可以改善癌症患者预后的治疗方法。分泌的3类信号量（SEMA3）被认为直接结合神经纤毛蛋白（NRP）共受体，而神经纤毛蛋白（NRP）共受体又与plexin（PLXN）受体信号相关并引发其，是癌症脉管系统的有效归一化剂。然而，据报道，SEMA3A也可通过NRP1触发不良副作用。我们合理设计并生成了一种安全的，可经肠胃外递送的，独立于NRP1的SEMA3A点突变体亚型，与野生型对应物不同，它以纳摩尔亲和力结合PLXNA4，并且在培养的内皮细胞中具有更大的生化和生物学活性。在体内，当在胰腺癌的小鼠模型中胃肠外给药时，不依赖NRP1的SEMA3A点突变体成功地使脉管系统正常化，抑制了肿瘤的生长，抑制了转移的扩散，并有效地提高了化疗的供应和抗癌活性。在年龄相关性黄斑变性的小鼠模型中，突变型SEMA3A也抑制了视网膜新血管形成。总之，突变体SEMA3A是一种血管正常化剂，可用于治疗癌症以及潜在的以病理性血管生成为特征的其他疾病。