Efficient therapy for refractory Pompe disease by mannose 6-phosphate analogue grafting on acid α-glucosidase - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Controlled Release Année : 2018

Efficient therapy for refractory Pompe disease by mannose 6-phosphate analogue grafting on acid α-glucosidase

Résumé

Pompe disease is a rare disorder due to deficiency of the acid a-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.
Fichier non déposé

Dates et versions

hal-01837837 , version 1 (12-07-2018)

Identifiants

Citer

Ilaria Basile, Afitz da Silva, Khaled El Cheikh, Anastasia Godefroy, Morgane Daurat, et al.. Efficient therapy for refractory Pompe disease by mannose 6-phosphate analogue grafting on acid α-glucosidase. Journal of Controlled Release, 2018, 269, pp.15-23. ⟨10.1016/j.jconrel.2017.10.043⟩. ⟨hal-01837837⟩
176 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Mastodon Facebook X LinkedIn More