Pompe disease is caused by acid alpha-glucosidase (GAA) deficiency, resulting in lysosomal glycogen accumulation. This disease is characterized by progressive skeletal muscle weakness, respiratory distress, and in the infantile-onset form, cardiomyopathy. The only approved treatment is enzyme replacement therapy (ERT) with human recombinant GAA. While ERT therapy extends life span, residual symptoms remain, with poor muscle uptake and immunogenicity limiting efficacy. We examined a novel Centyrin protein - short interfering ribonucleic acid (siRNA) conjugate targeting CD71 (transferrin receptor type 1, TfR1) and GYS1, a key enzyme involved in glycogen synthesis. Unlike existing ERTs designed to degrade aberrant glycogen deposits observed in Pompe patients, the CD71 Centyrin:Gys1 siRNA is designed to restore glycogen balance by inhibiting glycogen synthesis. To this end, we administered the CD71 Centyrin:Gys1 siRNA conjugate to the 6neo/6neo Pompe mouse model. Once bound to TfR1, siRNA-conjugated Centyrin is internalized into cells to facilitate gene knockdown. We found that treatment with this conjugate significantly reduced GYS1 protein expression, glycogen synthase enzymatic activity, and glycogen levels in muscle. In addition, impaired treadmill exercise performance of male Pompe mice was improved. These data suggest that Centyrin-mediated delivery of Gys1 siRNA may be an effective next generation therapy for late-onset Pompe disease or, in combination with ERT, for infantile-onset Pompe disease.

中文翻译：

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一种新的 CD71 Centyrin：Gys1 siRNA 靶向和递送平台可降低庞贝病小鼠模型中的糖原合成和糖原水平。


庞贝病是由酸性 α-葡萄糖苷酶 （GAA） 缺乏引起的，导致溶酶体糖原积累。这种疾病的特征是进行性骨骼肌无力、呼吸窘迫，以及婴儿发病形式的心肌病。唯一获批的治疗方法是人重组 GAA 的酶替代疗法 （ERT）。虽然 ERT 疗法延长了寿命，但残留症状仍然存在，肌肉摄取不良和免疫原性限制了疗效。我们检查了一种靶向 CD71 （转铁蛋白受体 1 型，TfR1） 和 GYS1 的新型 Centyrin 蛋白 - 短干扰核糖核酸 （siRNA） 偶联物，GYS1 是参与糖原合成的关键酶。与旨在降解庞贝病患者中观察到的异常糖原沉积的现有 ERT 不同，CD71 Centyrin：Gys1 siRNA 旨在通过抑制糖原合成来恢复糖原平衡。为此，我们将 CD71 Centyrin：Gys1 siRNA 偶联物施用到 6neo/6neo Pompe 小鼠模型中。一旦与 TfR1 结合，siRNA 偶联的 Centyrin 就会被内化到细胞中，以促进基因敲低。我们发现用这种偶联物治疗显着降低了肌肉中 GYS1 蛋白表达、糖原合酶酶活性和糖原水平。此外，雄性庞贝小鼠的跑步机运动表现受损得到改善。这些数据表明，Centyrin 介导的 Gys1 siRNA 递送可能是治疗晚发性庞贝病的有效下一代疗法，或者与 ERT 联合治疗婴儿发病的庞贝病。