Design of potent mannose 6-phosphate analogues for the functionalization of lysosomal enzymes to improve the treatment of pompe disease

Archive ouverte

El Cheikh, Khaled | Basile, Ilaria | da Silva, Afitz | Bernon, Coralie | Cerutti, Pierre | Salgues, Frédéric | Perez, Marc | Maynadier, Marie | Gary-Bobo, Magali | Caillaud, Catherine | Cerutti, Martine | Garcia, Marcel | Morere, Alain

Edité par CCSD ; Wiley-VCH Verlag -

Improving therapeutics delivery in enzyme replacement therapy (ERT) for lysosomal storage disorders is a challenge. Herein, we present the synthesis of novel analogues of mannose 6-phosphate (M6P), known as AMFAs and functionalized at the anomeric position for enzyme grafting. AMFAs are non-phosphate serum-resistant derivatives that efficiently bind the cation-independent mannose 6-phosphate receptor (CI-M6PR), which is the main pathway to address enzymes to lysosomes. One of the AMFAs was used to improve the treatment of the lysosomal myopathy Pompe disease, in which acid alpha-glucosidase (GAA) is defective. AMFA grafting on a M6P-free recombinant GAA led to a higher uptake of the GAA in adult Pompe fibroblasts in culture as compared to Myozyme, the M6P recombinant GAA. Moreover, the treatment of Pompe adult mice with the AMFA-grafted recombinant enzyme led to a remarkable improvement, even at low doses, in muscle functionality and regeneration, whereas Myozyme had limited efficacy.

• Description
• Sujet/Public
• Outil
• Outil d'anticipation
• Mémoire et thèse
• Gestion