Généthon, Évry, France.
Université Paris-Saclay, Univ Évry, Inserm, Généthon, Integrare research unit UMR_S951, 91000 Évry, France.
JCI Insight. 2024 May 16;9(11):e172614. doi: 10.1172/jci.insight.172614.
Glycogen storage disease type III (GSDIII) is a rare metabolic disorder due to glycogen debranching enzyme (GDE) deficiency. Reduced GDE activity leads to pathological glycogen accumulation responsible for impaired hepatic metabolism and muscle weakness. To date, there is no curative treatment for GSDIII. We previously reported that 2 distinct dual AAV vectors encoding for GDE were needed to correct liver and muscle in a GSDIII mouse model. Here, we evaluated the efficacy of rapamycin in combination with AAV gene therapy. Simultaneous treatment with rapamycin and a potentially novel dual AAV vector expressing GDE in the liver and muscle resulted in a synergic effect demonstrated at biochemical and functional levels. Transcriptomic analysis confirmed synergy and suggested a putative mechanism based on the correction of lysosomal impairment. In GSDIII mice livers, dual AAV gene therapy combined with rapamycin reduced the effect of the immune response to AAV observed in this disease model. These data provide proof of concept of an approach exploiting the combination of gene therapy and rapamycin to improve efficacy and safety and to support clinical translation.
糖原贮积病 III 型（GSDIII）是一种罕见的代谢紊乱疾病，由于糖原分支酶（GDE）缺乏所致。GDE 活性降低导致病理性糖原积累，从而导致肝脏代谢受损和肌肉无力。迄今为止，GSDIII 尚无治愈方法。我们之前报道过，需要 2 种不同的双 AAV 载体来纠正 GSDIII 小鼠模型中的肝脏和肌肉。在这里，我们评估了雷帕霉素联合 AAV 基因治疗的疗效。雷帕霉素与在肝脏和肌肉中表达 GDE 的新型双 AAV 载体同时治疗可在生化和功能水平上产生协同作用。转录组分析证实了协同作用，并基于纠正溶酶体损伤提出了一种可能的机制。在 GSDIII 小鼠肝脏中，双 AAV 基因治疗联合雷帕霉素可降低该疾病模型中观察到的 AAV 免疫反应的影响。这些数据为利用基因治疗和雷帕霉素联合的方法提供了概念验证，以提高疗效和安全性，并支持临床转化。
