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阻断圆圈1和2信号的单克隆抗体通过髓状细胞准病态的眼球新血管化

Luiz Henrique Geraldo^1,2, Yunling Xu³, Gaspard Mouthon⁴

¹Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.

Science translational medicine

|November 20, 2024

概括

针对ROBO1/2受体的新单克隆抗体阻断了病态的眼球新血管化. 这种方法有望通过调节髓状细胞活动和改善血视网膜屏障完整性来治疗导致失明的眼睛疾病.

科学领域:

眼科医生眼科眼科
免疫学免疫学免疫学
细胞生物学细胞生物学

背景情况:

SLIT-ROBO信号调节细胞功能,并与病态眼神新血管化有关,这是视力丧失的主要原因.
目前针对SLIT-ROBO介导的眼病的药理干预措施有限.

研究的目的:

开发和评估针对ROBO1和ROBO2细胞外域 (ECD) 的人类单克隆抗体 (mAbs),以抑制SLIT-ROBO信号传递.
评估这些mAbs在眼睛新血管化的临床前模型中的治疗潜力.

主要方法:

人类mAbs的发展与ROBO1和ROBO2ECD相对应.
在体外评估SLIT2信号的抗体抑制.
在氧气诱导视网膜病变 (OIR) 和激光诱导角膜新血管化 (CNV) 的小鼠模型中的体内评估.
对OIR视网膜的单细胞RNA测序,以分析细胞对抗体治疗的反应.
在髓状细胞中基因切除Robo1/2或PI3Kγ以确认作用机制.

主要成果:

一种抗ROBO1/2 mAb在体外有效抑制了SLIT2信号,并在OIR和CNV模型中降低了新血管化.
抗体治疗调节了内皮细胞,皮质细胞和髓质细胞,改善了血视网膜屏障的完整性,并防止了病态皮质细胞激活.
SLIT-ROBO抑制改变了髓状细胞种群,减少了病理激活,增加了神经保护子集.
在髓状细胞中对ROBO1/2或PI3Kγ的基因向模仿了抗ROBO1/2抗体的治疗作用.

结论:

阻断ROBO1/2抗体代表了一种有前途的治疗策略,用于盲目的眼睛疾病驱动由眼球新血管化.
骨髓状细胞在眼神血管疾病的发病过程中发挥着关键作用,它们通过SLIT-ROBO信号的调制是关键的治疗点.
针对SLIT-ROBO信号提供了一种新的方法来对抗各种盲目的眼睛疾病中的炎症和新血管化.

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