In vitro treatment of congenital disorder of glycosylation type Ia using PLGA nanoparticles loaded with GDP‑Man

Barbara Bortot, Eleonora De Martino, Alessandra Tesser, Blendi Ura, Barbara Ruozi, Michelangelo Aloisio, Stefania Biffi, Riccardo Addobbati, Giovanni Tosi, Diego Dolcetta, Giovanni Maria Severini

Research output: Contribution to journalArticlepeer-review


Congenital disorder of glycosylation (CDG) type Ia is a multisystem disorder that occurs due to mutations in the phosphomannomutase 2 (PMM2) gene, which encodes for an enzyme involved in the N‑glycosylation pathway. Mutated PMM2 leads to the reduced conversion of mannose‑6‑P to mannose‑1‑P, which results in low concentration levels of guanosine 5'‑diphospho‑D‑mannose (GDP‑Man), a nucleotide‑activated sugar essential for the construction of protein oligosaccharide chains. In the present study, an in vitro therapeutic approach was used, based on GDP‑Man‑loaded poly (D,L‑lactide‑co‑glycolide) (PLGA) nanoparticles (NPs), which were used to treat CDG‑Ia fibroblast cultures, thus bypassing the glycosylation pathway reaction catalysed by PMM2. To assess the degree of hypoglycosylation in vitro, the present study examined the activities of α‑mannosidase, β‑glucoronidase and β‑galactosidase in defective and normal fibroblasts. GDP‑Man (30 µg/ml GDP‑Man PLGA NPs) was incubated for 48 h with the cells and the specific activities of α‑mannosidase and β‑galactosidase were estimated at 69 and 92% compared with healthy controls. The residual activity of β‑glucoronidase increased from 6.5 to 32.5% and was significantly higher compared with that noted in the untreated CDG‑Ia fibroblasts. The glycosylation process of fibroblasts was also analysed by two‑dimensional electrophoresis. The results demonstrated that treatment caused the reappearance of several glycosylated proteins. The data in vitro showed that GDP‑Man PLGA NPs have desirable efficacy and warrant further evaluation in a preclinical validation animal model.
Original languageEnglish
Pages (from-to)262-272
Number of pages11
JournalInternational Journal of Molecular Medicine
Issue number1
Publication statusPublished - Jul 2019


  • Cells, Cultured
  • Congenital Disorders of Glycosylation/*drug therapy/genetics/metabolism/pathology
  • *Drug Carriers/chemistry/pharmacology
  • Fibroblasts
  • Glycosylation/drug effects
  • *Guanosine Diphosphate Mannose/chemistry/pharmacology
  • Humans
  • *Nanoparticles/chemistry/therapeutic use
  • Phosphotransferases (Phosphomutases)/*deficiency/genetics/metabolism
  • *Polylactic Acid-Polyglycolic Acid Copolymer/chemistry/pharmacology


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