Analysis of key immune-related genes and drug candidates in globoid cell leukodystrophy

doi:10.16352/j.issn.1001-6325.2025.06.0727

Abstract

Abstract: Objective To identify the key immune-related genes and potential drug targets of Krabbe disease by using neural stem cells(NSCs) derived from induced pluripotent stem cells(iPSCs) generated from patients with Krabbe disease. Methods 1)The transcriptome data of GLD-NSCs(GSE212512) was analyzed using GEO2R and Sangerbox; 2)Differential expression genes(DEGs) related to immunity were identified through various methods; 3)Functional enrichment and pathway analysis were performed using DAVID; 4)The protein-protein interaction network was constructed and analyzed using STRING and Cytoscape; 5)Key immune-related genes were determined through topological analysis; 6)Potential therapeutic drugs were screened using DGIdb and drug MAP data- bases; 7)Molecular docking was performed using CB-DOCK2. Results 1)Sixty-one immune-related DEGs were identified in patient NSCs, with GDNF, EGF, KDR, FGF10, and MET being identified as key immune-related genes; 2)Drug candidates with high binding affinity to these genes were identified, including gentamicin for GDNF, cetuximab for EGF,tivozanib for KDR, and capmatinib for MET. Conclusions The predictions suggest cetuximab, gentamicin, tivozanib, and capmatinib exhibit high binding affinity with EGF, GDNF, KDR, and MET, respectively, indicating their potential application value in GLD targeted therapy.

Key words: globoid cell leukodystrophy, Krabbe disease, neural stem cells, immune-related gene

CLC Number:

R318.04

LUO Guiyuan, LI Yang, ZHANG Ye, LYU Yafeng. Analysis of key immune-related genes and drug candidates in globoid cell leukodystrophy[J]. Basic & Clinical Medicine, 2025, 45(6): 727-734.

References 14

[1]	Bradbury AM, Bongarzone ER, Sands MS. Krabbe disease: New hope for an old disease[J]. Neurosci Lett, 2021, 752: 135841. doi: 10.1016/j.neulet.2021.135841.
[2]	Castaneda JA, Lim MJ, Cooper JD, et al. Immune system irregularities in lysosomal storage disorders[J]. Acta Neuropathol, 2008, 115: 159-174.
[3]	Sutter PA, Ménoret A, Jellison ER, et al. CD8+ T cell depletion prevents neuropathology in a mouse model of globoid cell leukodystrophy[J]. J Exp Med, 2023, 220:e20221862. doi: 10.1084/jem.20221862.
[4]	Wang W, Lv YF, Zhang YJ, et al. Generation of a human induced pluripotent stem cell line PUMCi001-A from a patient with Krabbe disease[J]. Stem Cell Res, 2020, 48: 101937. doi: 10.1016/j.scr.2020.101937.
[5]	Lv YF, Wang J, Cao CY, et al. Production and characterization of human induced pluripotent stem cell line(PUMCi002-A) from a Krabbe patient related control to study disease mechanisms associated with GALC mutation[J]. Stem Cell Res, 2022, 65: 102945. doi: 10.1016/j.scr.2022.102945.
[6]	Lv Y, Qin Y, Wang J, et al. Identifying altered developmental pathways in human globoid cell leukodystrophy iPSCs-derived NSCs using transcriptome profiling[J]. BMC Genomics, 2023, 24: 210. doi: 10.1186/s12864-023-09285-6.
[7]	Tian G, Cao C, Li S, et al. rAAV2-mediated restoration of GALC in neural stem cells from Krabbe patient-derived iPSCs[J]. Pharmaceuticals(Basel), 2023, 16:624. doi: 10.3390/ph16040624.
[8]	Shen W, Song Z, Zhong X, et al. Sangerbox: A comprehensive, interaction-friendly clinical bioinformatics analysis platform[J]. Imeta, 2022, 1: e36. doi: 10.1002/imt2.36.
[9]	Ma H, Bell KN, Loker RN. qPCR and qRT-PCR analysis: Regulatory points to consider when conducting biodistribution and vector shedding studies[J]. Mol Ther Methods Clin Dev, 2021, 20: 152-168.
[10]	Sherman BT, Hao M, Qiu J, et al. DAVID: a web server for functional enrichment analysis and functional annotation of gene lists(2021 update)[J]. Nucleic Acids Res, 2022, 50: W216-W221.
[11]	Szklarczyk D, Franceschini A, Wyder S, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life[J]. Nucleic Acids Res, 2015, 43(Database issue): D447-D452.
[12]	Griffith M, Griffith OL, Coffman AC, et al. DGIdb: mining the druggable genome[J]. Nat Methods, 2013, 10:1209-1210.
[13]	Fu C, Jin G, Gao J, et al. DrugMap Central: an on-line query and visualization tool to facilitate drug repositioning studies[J]. Bioinformatics, 2013, 29: 1834-1836.
[14]	Liu Y, Yang X, Gan J, et al. CB-Dock2: improved protein-ligand blind docking by integrating cavity detection, docking and homologous template fitting[J]. Nucleic Acids Res, 2022, 50: W159-W164.