Snyder–Robinson syndrome (SRS) results from mutations in spermine synthase (SMS), which converts the polyamine spermidine into spermine. Affecting primarily males, common manifestations of SRS include intellectual disability, osteoporosis, hypotonia, and seizures. Symptom management is the only treatment. Reduced SMS activity causes spermidine accumulation while spermine levels are reduced. The resulting exaggerated spermidine:spermine ratio is a biochemical hallmark of SRS that tends to correlate with symptom severity. Our studies aim to pharmacologically manipulate polyamine metabolism to correct this imbalance as a therapeutic strategy for SRS. Here we report the repurposing of 2-difluoromethylornithine (DFMO), an FDA-approved inhibitor of polyamine biosynthesis, in rebalancing spermidine:spermine ratios in SRS patient cells. Mechanistic in vitro studies demonstrate that, while reducing spermidine biosynthesis, DFMO also stimulates the conversion of spermidine into spermine in hypomorphic SMS cells and induces uptake of exogenous spermine, altogether reducing the aberrant ratios. In a Drosophila SRS model characterized by reduced lifespan, DFMO improves longevity. As nearly all SRS patient mutations are hypomorphic, these studies form a strong foundation for translational studies with significant therapeutic potential.

中文翻译：

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二氟甲基鸟氨酸重新平衡斯奈德-罗宾逊综合征中异常的多胺比率


斯奈德-罗宾逊综合征 (SRS) 是由精胺合成酶 (SMS) 突变引起的，该酶将多胺亚精胺转化为精胺。 SRS 主要影响男性，常见症状包括智力障碍、骨质疏松、肌张力低下和癫痫发作。症状管理是唯一的治疗方法。 SMS 活动减少会导致亚精胺积累，同时精胺水平也会降低。由此产生的亚精胺：精胺比例过高是 SRS 的生化标志，往往与症状严重程度相关。我们的研究旨在通过药理学调控多胺代谢来纠正这种不平衡，作为 SRS 的治疗策略。在此，我们报告了 2-二氟甲基鸟氨酸 (DFMO)（一种 FDA 批准的多胺生物合成抑制剂）的重新用途，用于重新平衡 SRS 患者细胞中的亚精胺：精胺比例。体外机制研究表明，在减少亚精胺生物合成的同时，DFMO 还能刺激亚精胺在亚形态 SMS 细胞中转化为精胺，并诱导外源精胺的摄取，从而总体降低异常比例。在以寿命缩短为特征的果蝇SRS 模型中，DFMO 可以延长寿命。由于几乎所有 SRS 患者突变都是亚等位性突变，这些研究为具有显着治疗潜力的转化研究奠定了坚实的基础。