The leukodystrophy vanishing white matter (VWM) is characterized by chronic and episodic acute neurological deterioration. Curative treatment is presently unavailable. Pathogenic variants in the genes encoding eukaryotic initiation factor 2B (eIF2B) cause VWM and deregulate the integrated stress response (ISR). Previous studies in VWM mouse models showed that several ISR-targeting compounds ameliorate clinical and neuropathological disease hallmarks. It is unclear which ISR components are suitable therapeutic targets. In this study, effects of 4-phenylbutyric acid, tauroursodeoxycholic acid, or pridopidine (PDPD), with ISR targets upstream or downstream of eIF2B, were assessed in VWM mice. In addition, it was found that the composite ataxia score represented motor decline of VWM mice more accurately than the previously used neuroscore. 4-phenylbutyric acid and tauroursodeoxycholic acid did not improve VWM disease hallmarks, whereas PDPD had subtle beneficial effects on motor skills. PDPD alone does not suffice as treatment in VWM mice but may be considered for combination therapy. Also, treatments aimed at ISR components upstream of eIF2B do not improve chronic neurological deterioration; effects on acute episodic decline remain to be investigated.

中文翻译：

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普利多匹定巧妙地改善白质消失小鼠模型的运动技能。

脑白质营养不良性白质消失（VWM）的特点是慢性和阵发性急性神经功能恶化。目前尚无治愈性治疗方法。编码真核起始因子 2B (eIF2B) 的基因中的致病性变异会导致 VWM 并失调综合应激反应 (ISR)。先前对 VWM 小鼠模型的研究表明，几种 ISR 靶向化合物可改善临床和神经病理学疾病特征。目前尚不清楚哪些 ISR 成分是合适的治疗靶点。在这项研究中，在 VWM 小鼠中评估了 4-苯基丁酸、牛磺熊去氧胆酸或普利多匹定 (PDPD) 以及 eIF2B 上游或下游 ISR 靶点的影响。此外，还发现复合共济失调评分比之前使用的神经评分更准确地代表了 VWM 小鼠的运动衰退。4-苯基丁酸和牛磺熊去氧胆酸并不能改善 VWM 疾病特征，而 PDPD 对运动技能有微妙的有益影响。单独使用 PDPD 不足以治疗 VWM 小鼠，但可以考虑联合治疗。此外，针对 eIF2B 上游 ISR 成分的治疗并不能改善慢性神经功能恶化；对急性发作性衰退的影响仍有待研究。