Glycogen storage disease type 1a (GSD1a) is caused by a congenital deficiency of glucose-6-phosphatase-α (G6Pase-α, encoded by G6PC), which is primarily associated with life-threatening hypoglycemia. Although strict dietary management substantially improves life expectancy, patients still experience intermittent hypoglycemia and develop hepatic complications. Emerging therapies utilizing new modalities such as adeno-associated virus and mRNA with lipid nanoparticles are under development for GSD1a but potentially require complicated glycemic management throughout life. Here, we present an oligonucleotide-based therapy to produce intact G6Pase-α from a pathogenic human variant, G6PC c.648G>T, the most prevalent variant in East Asia causing aberrant splicing of G6PC. DS-4108b, a splice-switching oligonucleotide, was designed to correct this aberrant splicing, especially in liver. We generated a mouse strain with homozygous knockin of this variant that well reflected the pathophysiology of patients with GSD1a. DS-4108b recovered hepatic G6Pase activity through splicing correction and prevented hypoglycemia and various hepatic abnormalities in the mice. Moreover, DS-4108b had long-lasting efficacy of more than 12 weeks in mice that received a single dose and had favorable pharmacokinetics and tolerability in mice and monkeys. These findings together indicate that this oligonucleotide-based therapy could provide a sustainable and curative therapeutic option under easy disease management for GSD1a patients with G6PC c.648G>T.

中文翻译：

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剪接转换寡核苷酸治疗可改善 G6PC c.648G>T 小鼠的 1a 型糖原累积病。

1a 型糖原贮积病 (GSD1a) 是由先天性葡萄糖-6-磷酸酶-α（G6Pase-α，由 G6PC 编码）缺乏引起的，主要与危及生命的低血糖有关。尽管严格的饮食管理大大提高了预期寿命，但患者仍然会出现间歇性低血糖并出现肝脏并发症。利用腺相关病毒和带有脂质纳米颗粒的 mRNA 等新模式的新兴疗法正在针对 GSD1a 进行开发，但可能需要在整个生命周期进行复杂的血糖管理。在这里，我们提出了一种基于寡核苷酸的疗法，从致病性人类变异 G6PC c.648G>T 产生完整的 G6Pase-α，G6PC c.648G>T 是东亚最常见的变异，导致 G6PC 剪接异常。DS-4108b 是一种剪接转换寡核苷酸，旨在纠正这种异常剪接，尤其是在肝脏中。我们生成了具有该变体纯合敲入的小鼠品系，它很好地反映了 GSD1a 患者的病理生理学。DS-4108b 通过剪接校正恢复了肝脏 G6Pase 活性，并预防了小鼠的低血糖和各种肝脏异常。此外，DS-4108b 在单剂量小鼠中具有超过 12 周的持久疗效，并且在小鼠和猴子中具有良好的药代动力学和耐受性。这些发现共同表明，这种基于寡核苷酸的疗法可以在轻松的疾病管理下为患有 G6PC c.648G>T 的 GSD1a 患者提供可持续且有疗效的治疗选择。