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- Title
Design of Potent Mannose 6-Phosphate Analogues for the Functionalization of Lysosomal Enzymes To Improve the Treatment of Pompe Disease.
- Authors
El Cheikh, Khaled; Basile, Ilaria; Da Silva, Afitz; Bernon, Coralie; Cérutti, Pierre; Salgues, Frédéric; Perez, Marc; Maynadier, Marie; Gary ‐ Bobo, Magali; Caillaud, Catherine; Cérutti, Martine; Garcia, Marcel; Morère, Alain
- Abstract
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 α-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.
- Subjects
MANNOSE 6-phosphate; LYSOSOMES; GLYCOGEN storage disease type II; FUNCTIONAL groups; GLUCOSIDASES; RECOMBINANT proteins; PHYSIOLOGY; THERAPEUTICS
- Publication
Angewandte Chemie, 2016, Vol 128, Issue 47, p14994
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201607824