美国格拉德斯通研究院Isha H. Jain研究小组发现HypoxyStat是一种增加氧血红蛋白亲和力的小分子缺氧疗法。相关论文发表在2025年2月17日出版的《细胞》杂志上。
该课题组研究人员之前已经证明，慢性吸入性缺氧对线粒体Leigh综合征的主要动物模型Ndufs4敲除（KO）小鼠具有显著的治疗作用。随后的工作将这一发现扩展到其他线粒体疾病和更常见的疾病。
然而，气体疗法固有的挑战阻碍了他们的发现迅速转化为临床。该研究组测试了一种小分子（以下称为HypoxyStat），它可以增加血红蛋白对氧的结合亲和力，从而减少氧向组织的卸载。每日口服剂量的HypoxyStat引导呼吸常氧（21% O2）空气的小鼠全体性缺氧。在发病前给药，这种治疗显著延长了Ndufs4 KO小鼠的寿命，并挽救了疾病的其他方面，包括行为、体重、神经病理学和体温。HypoxyStat也能够在非常晚的阶段逆转疾病，因此作为一种临床易处理的缺氧治疗形式。
附：英文原文
Title: HypoxyStat, a small-molecule form of hypoxia therapy that increases oxygen-hemoglobin affinity
Author: Skyler Y. Blume, Ankur Garg, Yolanda Martí-Mateos, Ayush D. Midha, Brandon T.L. Chew, Baiwei Lin, Cecile Yu, Ryan Dick, Patrick S. Lee, Eva Situ, Richa Sarwaikar, Eric Green, Vyas Ramanan, Gijsbert Grotenbreg, Maarten Hoek, Christopher Sinz, Isha H. Jain
Issue&Volume: 2025-02-17
Abstract: We have previously demonstrated that chronic inhaled hypoxia is remarkably therapeutic in the premier animal model of mitochondrial Leigh syndrome, the Ndufs4 knockout (KO) mouse. Subsequent work has extended this finding to additional mitochondrial diseases and more common conditions. However, challenges inherent to gas-based therapies have hindered the rapid translation of our findings to the clinic. Here, we tested a small molecule (hereafter termed HypoxyStat) that increases the binding affinity of hemoglobin for oxygen, thereby decreasing oxygen offloading to tissues. Daily oral dosing of HypoxyStat caused systemic hypoxia in mice breathing normoxic (21% O2) air. When administered prior to disease onset, this treatment dramatically extended the lifespan of Ndufs4 KO mice and rescued additional aspects of disease, including behavior, body weight, neuropathology, and body temperature. HypoxyStat was also able to reverse disease at a very late stage, thereby serving as a clinically tractable form of hypoxia therapy.
DOI: 10.1016/j.cell.2025.01.029
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00098-4