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

Int J Mol Med. 2019 Jul;44(1):262-272. doi: 10.3892/ijmm.2019.4199. Epub 2019 May 16.


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.

MeSH terms

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


  • Drug Carriers
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Guanosine Diphosphate Mannose
  • Phosphotransferases (Phosphomutases)
  • phosphomannomutase 2, human

Supplementary concepts

  • Congenital disorder of glycosylation type 1A