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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02802-4

摘要内容如下：

血管内皮屏障功能受损是糖尿病并发症的显著特征，如威胁视力的糖尿病性黄斑水肿（DME）。目前的DME护理标准可以控制疾病的各个方面，但需要频繁的玻璃体内给药，并且在大部分患者中效果不佳。在这里，我们提供的证据表明，视网膜中衰老细胞负荷的增加触发了DME病理的主要特征，并对DME患者进行了抗衰老治疗的初步试验。在细胞培养模型中，持续的高血糖引起血管内皮细胞亚群的细胞衰老，表现出与屏障功能低下相关的跨内皮连接紊乱，并导致微炎症。DME小鼠模型中衰老细胞的药理学清除可减少糖尿病诱导的视网膜血管渗漏并保护视网膜功能然后，我们在抗血管内皮生长因子治疗不再被认为有益的晚期DME患者中进行了UBX1325（Foselutoclax）（一种Bcl-XL的抗衰老小分子抑制剂）的1期单次递增剂量安全性研究。评估UBX1325的安全性和耐受性的主要目标已经实现。总之，我们的数据表明，用Bcl-XL抑制剂治疗糖尿病视网膜中的衰老细胞可能为DME提供长期的疾病改善干预。这一假设需要在更大规模的临床试验中得到验证。ClinicalTrials.gov标识符：NCT04537884。

英文原文如下：

Abstracts

Compromised vascular endothelial barrier function is a salient feature of diabetic complications such as sight-threatening diabetic macular edema (DME). Current standards of care for DME manage aspects of the disease, but require frequent intravitreal administration and are poorly effective in large subsets of patients. Here we provide evidence that an elevated burden of senescent cells in the retina triggers cardinal features of DME pathology and conduct an initial test of senolytic therapy in patients with DME. In cell culture models, sustained hyperglycemia provoked cellular senescence in subsets of vascular endothelial cells displaying perturbed transendothelial junctions associated with poor barrier function and leading to micro-inflammation. Pharmacological elimination of senescent cells in a mouse model of DME reduces diabetes-induced retinal vascular leakage and preserves retinal function. We then conducted a phase 1 single ascending dose safety study of UBX1325 (foselutoclax), a senolytic small-molecule inhibitor of BCL-xL, in patients with advanced DME for whom anti-vascular endothelial growth factor therapy was no longer considered beneficial. The primary objective of assessment of safety and tolerability of UBX1325 was achieved. Collectively, our data suggest that therapeutic targeting of senescent cells in the diabetic retina with a BCL-xL inhibitor may provide a long-lasting, disease-modifying intervention for DME. This hypothesis will need to be verified in larger clinical trials. ClinicalTrials.gov identifier: NCT04537884 .

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