bims-meglyc 2025-04-06 papers

Biochim Biophys Acta Mol Cell Res. 2025 Mar 30. pii: S0167-4889(25)00053-9. [Epub ahead of print]1872(5): 119948

Beneficial effects of Glc-1,6-P2 modulation on mutant phosphomannomutase-2.

Maria Monticelli, Debora Paris, Maria Chiara Monti, Elva Morretta, Zuzana Pakanova, Marek Nemcovic, Rebeka Kodrikova, Maria Vittoria Cubellis, Giuseppina Andreotti.

The metabolite Glucose-1,6-bisphosphate (Glc-1,6-P2) plays a vital role in human metabolism, and is a crucial activator and stabilizer for phosphomannomutase-2 (PMM2) - mutations within this protein propagate the most common congenital disorder of glycosylation (PMM2-CDG). In vivo, Glc-1,6-P2 is hydrolysed by phosphomannomutase-1 (PMM1), predominantly in the brain, under the influence of inosine monophosphate (IMP). In the present study, we employed knock-out PMM1 in Arg141His/Phe119LeuPMM2 patient-derived fibroblasts and investigated the phenotypic improvement. Increased Glc-1,6-P2 was associated with glycosylation enhancement, confirmed by glycan profiling. Previously identified PMM2-CDG biomarkers, such as LAMP1, PTX3 and lysosomal enzymes showed empirical imrovement- these findings were corroborated by metabolomic and proteomic analysis. Moreover, our results support the potential of Glc-1,6-P2 modulation for PMM2-CDG, potentiating novel perspectives in drug discovery.

Keywords: Biomarkers; Glucose-1,6-bisphosphate; Glycomics; Metabolomics; PMM1; PMM2-CDG; Proteomics

DOI: https://doi.org/10.1016/j.bbamcr.2025.119948

Clin Chem. 2025 Apr 03. 71(4): 523-525

Mannose Phosphate Isomerase Deficiency-Congenital Disorder of Glycosylation (MPI-CDG) Type 1b: Familial Case of Thrombophilia and Liver Disorder.

Franklin Ducatez, Elisa Minacori, Sandrine Vuillaumier Barrot, Gaëtan Sauvêtre, Ivana Dabaj.

DOI: https://doi.org/10.1093/clinchem/hvaf009

Drug Discov Today. 2025 Mar 28. pii: S1359-6446(25)00059-5. [Epub ahead of print] 104346

Drug development for neglected ultra-rare diseases of no commercial interest: Challenges and opportunities.

Joseph A Katakowski, Juan C López.

Ultra-rare diseases, particularly those that affect a few hundred patients worldwide, are of little commercial interest to the pharmaceutical industry. Patient-led organizations have made remarkable progress in funding the early-stage, academic development of therapies for such neglected ultra-rare conditions. But the long and difficult path to translate most academic proof-of-concept studies into approved medicines means that very few therapies ever reach patients. Here, we discuss some of the roadblocks to the development of therapeutics for conditions of limited commercial interest and propose ways to overcome these obstacles.

Keywords: patient advocacy; philanthropy; ultra-rare disease

DOI: https://doi.org/10.1016/j.drudis.2025.104346