简介:
- 作者: Zhu Shi , Jinrui Li , Ziying Feng , Cheng Fang , Yueqing Wang , Linhui Qiu , Jingjing Liu , Feng Wang , Zhen-Ni Guo , Yi Yang , Kaibin Huang , Junlei Chang , Yinzhong Ma
- 杂志: European Heart Journal
- Doi: https://doi.org/10.1093/eurheartj/ehaf959
- 出版日期: 2025/12/26
摘要
Ischaemic stroke remains a major cause of disability and mortality, with current treatments constrained by a narrow therapeutic time window and the risk of complications such as haemorrhagic transformation and reperfusion injury. This study investigates the role of Dickkopf-related protein 2 (DKK2) in the pathophysiology of ischaemic stroke, exploring its potential as a therapeutic target.
Dickkopf-related protein 2 levels were analysed in a murine model of transient middle cerebral artery occlusion (tMCAO) and in stroke patients with large vessel occlusion undergoing endovascular treatment. The causal role of DKK2 was explored using genetic knockout and viral targeting strategies to manipulate its expression, and using pharmacological approaches to assess its therapeutic potential. Mechanistic studies focused on the regulation of DKK2 by retinoid X receptor-alpha (RXRα) and its effects on neuronal injury and blood–brain barrier (BBB) integrity.
Dickkopf-related protein 2 was significantly up-regulated in both the brain and serum of mice after tMCAO. Serum DKK2 levels were elevated in stroke patients with larger infarct volumes, ICH, and worse functional outcomes. In murine models, systemic or neuron-specific DKK2 overexpression exacerbated infarction, neurological deficits, and BBB disruption, while genetic ablation or monoclonal antibody-mediated inhibition of DKK2 substantially ameliorated these parameters. Mechanistically, DKK2 was up-regulated in neurons by RXRα under ischaemia/reperfusion conditions both in vitro and in vivo, and this contributed to neuronal death and BBB disruption through suppression of canonical Wnt signalling.
Dickkopf-related protein 2 plays a critical role in the progression of ischaemic stroke by modulating neuronal survival and BBB integrity. Targeting DKK2 represents a promising therapeutic approach to ischaemic brain injury, and the observational human data extend experimental findings to human cerebrovascular pathology, suggesting translational potential.
关于派真
作为一家专注于AAV 技术十余年，深耕基因治疗领域的CRO&CDMO，派真生物可提供从载体设计、构建到 AAV、慢病毒和 mRNA 服务的一站式解决方案。凭借深厚的技术实力、卓越的运营管理和高标准的服务交付，我们为全球客户提供一站式CMC解决方案，包括从早期概念验证、成药性评估到IIT、IND及BLA的各个阶段。
凭借我们独立知识产权的π-alphaTM 293 细胞AAV高产技术平台，我们能将AAV产量提高多至10倍，每批次产量可达1×10¹⁷vg，以满足多样化的商业化和临床项目需求。此外，我们定制化的mRNA和脂质纳米颗粒（LNP）产品及服务覆盖药物和疫苗开发的各个阶段，从研发到符合GMP的生产，提供端到端的一站式解决方案。
