Zinc for GNAO1 encephalopathy: Preclinical profiling and a clinical case.

IF 12.8 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Med Pub Date : 2024-08-13 DOI:10.1016/j.medj.2024.07.023

Yonika A Larasati, Moritz Thiel, Alexey Koval, Denis N Silachev, Anne Koy, Vladimir L Katanaev

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引用次数: 0

Abstract

Background: De novo pathogenic variants in GNAO1-the gene encoding the major neuronal G protein Gαo-cause pediatric encephalopathies and other neurological deficiencies largely refractory to available therapies. Zn²⁺ emerged to restore guanosine triphosphate hydrolysis and cellular interactions of pathogenic Gαo; dietary zinc salt supplementation improves lifespan and motoric function in a Drosophila disease model.

Methods: Using biochemical, animal, and first-in-human studies, we provide support for the patient stratification and application of zinc acetate in GNAO1-associated disorders.

Findings: We show that 16 different pathogenic missense variants cluster in three distinct groups in their responsiveness to Zn²⁺, and we provide the safety study in a mouse disease model. We further describe treatment of a 3-year-old patient with the common pathogenic GNAO1 variant c607G>A, p.Gly203Arg with oral 50 mg zinc (in the form of zinc acetate) daily, as applied in Wilson's disease. During 11 months of treatment, the patient shows cessation of daily dyskinetic crises, improved Burke-Fahn Marsden Dystonia Rating Scale movement score, reduction in epileptic seizures, and an excellent safety profile.

Conclusions: Our findings warrant a large-scale clinical trial and might set the new standard of care for GNAO1-related disorders.

Funding: This work was funded by the Russian Science Foundation (grant #21-15-00138) and GNAO1 España.

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锌治疗 GNAO1 脑病：临床前分析和一个临床病例。

背景：GNAO1--编码主要神经元G蛋白Gαo的基因--中的新致病变体会导致小儿脑病和其他神经系统缺陷，现有疗法在很大程度上难以奏效。Zn2+ 的出现恢复了致病 Gαo 的三磷酸鸟苷水解和细胞相互作用；在果蝇疾病模型中，膳食锌盐补充能改善果蝇的寿命和运动功能：通过生化、动物和首次人体研究，我们为患者分层和醋酸锌在GNAO1相关疾病中的应用提供了支持：我们的研究结果表明，16 种不同的致病性错义变体对 Zn2+ 的反应分为三组，我们还提供了小鼠疾病模型的安全性研究。我们进一步描述了对一名患有常见致病性 GNAO1 变体 c607G>A，p.Gly203Arg 的 3 岁患者每天口服 50 毫克锌（以醋酸锌的形式）的治疗情况，这种治疗方法适用于威尔逊氏病。在11个月的治疗过程中，患者停止了每天的运动障碍危机，改善了Burke-Fahn Marsden肌张力障碍评分量表的运动评分，减少了癫痫发作，而且安全性极佳：我们的研究结果值得进行大规模临床试验，并有可能成为治疗GNAO1相关疾病的新标准：本研究由俄罗斯科学基金会（Grant #21-15-00138）和西班牙 GNAO1 基金会资助。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Med MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

17.70

自引率

0.60%

发文量

102

期刊介绍： Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically. Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.