bims-meglyc 2025-03-23 papers

Issue of 2025–03–23
three papers selected by
Silvia Radenkovic, UMC Utrecht

Gene Ther. 2025 Mar 17.

AAV-based gene replacement therapy prevents and halts manifestation of abnormal neurological phenotypes in a novel mouse model of PMM2-CDG.

Mian-Ling Zhong, Kent Lai.

Inherited Phosphomannomutase 2 (PMM2) deficiency, also known as PMM2-CDG, is the most prevalent N-linked congenital disorder of glycosylation (CDG), occurring in approximately 1 in 20,000 individuals in certain populations. Patients exhibit a spectrum of symptoms, with neurological involvement being a prominent feature, often manifesting as the initial clinical sign, and can range from isolated neurological deficits to severe multi-organ dysfunction. Given the absence of curative treatments and a high mortality rate before the age of two, alongside considerable lifelong morbidity, there is an urgent need for innovative therapeutic approaches. To address this unmet need, we developed a tamoxifen-inducible Pmm2 knockout (KO) mouse model with widespread tissue deficiency of Pmm2 expression. Characterization of the mouse model to-date revealed distinct neurological phenotypes relevant to PMM2-CDG, as assessed by the Composite Phenotype Scoring System and Open Field Test. Notably, PMM2 augmentation through AAV9-PMM2 gene replacement therapy prevented and halted the disease-relevant neurological phenotypes induced by Pmm2 KO in the animals. These findings underscored the promise of AAV9-PMM2 gene replacement in managing PMM2-CDG.

DOI: https://doi.org/10.1038/s41434-025-00525-w

Comput Biol Med. 2025 Mar 20. pii: S0010-4825(25)00393-2. [Epub ahead of print]190 110042

Computational profiling of molecular biomarkers in congenital disorders of glycosylation Type-I and binding analysis of Ginkgolide A with P4HB.

Muhammad Rahiyab, Ishaq Khan, Syed Shujait Ali, Zahid Hussain, Shahid Ali, Arshad Iqbal.

AIMS: Congenital disorders of glycosylation (CDG) comprise a diverse group of genetic diseases characterized by aberrant glycosylation that leads to severe multi-systematic effects. Despite advancements in understanding the underlying molecular mechanisms, curative options remain limited. This study employed computational methods to identify key molecular biomarkers for CDG-I and examine the pharmacological effects of Ginkgolide A (GA), a potent bioactive natural compound.
METHODS: We analyzed the GSE8440 microarray dataset to discover differentially expressed genes (DEGs) in patients compared to healthy individuals with CDG-I utilizing GEO2R. Functional enrichments, including gene ontologies (GO) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses, were conducted to contextualize the biological mechanisms and molecular signatures involved in CDG-I (Congenital Disorders of Glycosylation Type-1). The protein-protein interaction (PPI) network for DEGs was constructed using the STRING database, and the central hub genes within the PPI network were identified using Cytohubba. Furthermore, the 3D structure of the top hub gene (P4HB) was predicted by using the Robetta server. The CASTp was employed to evaluate the active sites. Molecular docking of P4HB with GA was carried out to investigate the binding affinity using the PyRx tool, and the stability of the docked complex was validated through MD simulation. The pharmacokinetics, toxicity, and bioactivity score of GA were comprehensively assessed using SwissADME, ProTox-II, and Molinspiration.
RESULTS: Our findings indicated 247 significant DEGs, including 146 up-regulated and 101 down-regulated genes. GO and KEGG pathway analyses confirmed that the up-regulated and hub genes were strongly associated with protein folding, glycoprotein processing in the endoplasmic reticulum, and endoplasmic reticulum stress (ER) pathways. P4HB emerged as the top hub gene in CDG-I, playing a significant role in protein folding and ER stress. The 3D structure of P4HB was refined and validated, achieving 95.8 % residues in the most favored region of the Ramachandran plot, with an overall quality of 92.97 %. The CASTp server predicted the largest active site with an area of 2243.660 Å2 and a volume of 3236.584 Å3. Molecular docking revealed that GA has a strong binding affinity with P4HB (-8.9 kcal/mol). The ADME (Absorption, Distribution, Metabolism, Excretion) and toxicity assessments confirmed promising drug-like characteristics, excellent bioavailability, and minimal toxicity risk.
CONCLUSION: This study emphasizes GA as a potential treatment possibility option to alleviated CDG-I pathology by targeting protein misfolding and ER stress, which are fundamental aspects of the disease. Additionally, our findings indicate that P4HB is a critical molecular target in CDG-I. These results pave the way for future preclinical and clinical investigations aimed at advancing the targeted and tailored treatments for CDG.

Keywords: ADME; Active sites; CDG-I; GA; GO and KEGG pathways; Hub gene (P4HB); MD simulation; Microarray dataset (GSE8440)

DOI: https://doi.org/10.1016/j.compbiomed.2025.110042

Hepatol Commun. 2025 Apr 01. pii: e0671. [Epub ahead of print]9(4):

Mannose reduces fructose metabolism and reverses MASH in human liver slices and murine models in vivo.

John G Hong, Joshaya Trotman, Yvette Carbajal, Poulomi Dey, Mariel Glass, Victoria Sclar, Isaac L Alter, Peng Zhang, Liheng Wang, Li Chen, Mathieu Petitjean, Dipankar Bhattacharya, Shuang Wang, Scott L Friedman, Charles DeRossi, Jaime Chu.

BACKGROUND: Fibrosis drives liver-related mortality in metabolic dysfunction-associated steatohepatitis (MASH), yet we have limited medical therapies to target MASH-fibrosis progression. Here we report that mannose, a simple sugar, attenuates MASH steatosis and fibrosis in 2 robust murine models and human liver slices.
METHODS: The well-validated fat-and-tumor MASH murine model for liver steatosis and fibrosis was employed. Mannose was supplied in the drinking water at the start ("Prevention" group) or at week 6 of the 12-week MASH regimen ("Therapy" group). The in vivo antifibrotic effects of mannose supplementation were tested in a second model of carbon tetrachloride (CCl4)-induced liver fibrosis. A quantitative and automated digital pathology approach was used to comprehensively assess steatosis and fibrosis phenotypes. Mannose was also tested in vitro in human and primary mouse hepatocytes conditioned with free fatty acids alone or with fructose, and human precision-cut liver slices from patients with end-stage MASH cirrhosis.
RESULTS: Oral mannose supplementation improved liver fibrosis in vivo in both fat-and-tumor MASH and CCl4 mouse models, as well as in human precision-cut liver slice MASH samples. Mannose also reduced liver steatosis in fat-and-tumor MASH mice, and in human and mouse hepatocytes in vitro. Ketohexokinase, the main enzyme in fructolysis, was decreased with mannose in whole mouse liver, cultured hepatocytes, and human precision-cut liver slices. Removal of fructose or overexpression of ketohexokinase each abrogated the antisteatotic effects of mannose.
CONCLUSIONS: This study identifies mannose as a novel therapeutic candidate for MASH that mitigates steatosis by dampening hepatocyte ketohexokinase expression and exerts independent antifibrotic effects in 2 mouse models and human liver tissue slices.

DOI: https://doi.org/10.1097/HC9.0000000000000671