Pompe disease is a rare disorder due to deficiency of the acid α-glucosidase (GAA) treated by enzyme replacement therapy. The present authorized treatment with rhGAA, the recombinant human enzyme, provides an important benefit in the infantile onset; however, the juvenile and adult forms of the disease corresponding to > 80% of the patients are less responsive to this treatment. This resistance has been mainly attributed to an insufficiency of mannose 6-phosphate residues in rhGAA to address lysosomes through the cation-independent mannose 6-phosphate receptor (CI-M6PR). As yet, several attempts to improve the enzyme delivery by increasing the number of mannose 6-phosphate on the enzyme were poorly effective on the late onset form of the disease. Here, we show that chemical conjugation of a synthetic analogue of the mannose 6-phosphate, named AMFA, onto rhGAA improves the affinity for CI-M6PR and the uptake of the enzyme in fibroblasts and myoblasts of adult Pompe patients. More importantly, only the conjugated rhGAA-AMFA was effective in aged Pompe mice when compared to rhGAA. Weekly treatment with 5–20 mg·kg^− 1 rhGAA-AMFA provided major improvements of the motor function and of the myofiber structure, whereas rhGAA was inactive. Finally, AMFA addition did not induce supplementary immune response to the enzyme. This modified enzyme, displaying a muscle recovery in aged Pompe mice that was never attained before, could be considered as a potential therapy for the late onset Pompe disease.

由于通过酶替代疗法治疗的酸性α-葡萄糖苷酶（GAA）缺乏，庞贝病是一种罕见的疾病。重组人酶rhGAA的当前授权治疗对婴儿发作起了重要作用。但是，对应于80％以上患者的青少年和成人疾病对该治疗的反应较弱。这种抗性主要归因于rhGAA中的甘露糖6-磷酸残基不足，无法通过不依赖阳离子的甘露糖6-磷酸受体（CI-M6PR）处理溶酶体。迄今为止，通过增加酶上6-磷酸甘露糖的数量来改善酶递送的几种尝试在该疾病的晚期发作形式上效果不佳。在这里，我们显示了甘露糖6-磷酸酯的合成类似物的化学共轭，rhGAA上的一种名为AMFA的化合物可改善对CI-M6PR的亲和力，并改善成人庞贝患者成纤维细胞和成肌细胞中酶的吸收。更重要的是，与rhGAA相比，只有缀合的rhGAA-AMFA在老年Pompe小鼠中有效。每周治疗5–20 mg·kg^{− 1} rhGAA-AMFA显着改善了运动功能和肌纤维结构，而rhGAA未激活。最后，添加AMFA不会诱导对该酶的补充免疫反应。这种修饰的酶在老年庞贝小鼠中显示出肌肉恢复，这是以前从未达到的，可以被认为是晚期庞贝疾病的一种潜在疗法。