Adjunctive nebulization of Idursulfase to intravenous treatment enhances cardiac proteome adaptations in IDS-KO mice
- 1Duke University School of Medicine
Abstract
Mucopolysaccharidosis Type II (MPS-II) is a rare X-linked lysosomal storage disorder, characterized by deficiency of the lysosomal hydrolase iduronate 2-sulphatase (IDS). Cardiac impairments contribute to mortality in patients. Enzyme replacement therapy (ERT) with Idursulfase is a promising treatment for the cardiac dysfunction. We compared the proteome changes following intravenous (IV) with and without adjunct nebulized ERT in IDS-KO mice. Male mice were assigned to 4 groups: 1) WT IV + nebulized saline (WT; n=8); 2) IDS-KO IV + nebulized saline (KO; n=5); 3) IDS-KO IV Idursulfase (1 mg/kg; KO-IV, n=5); 4) IDS-KO IV (1 mg/kg) + nebulized Idursulfase (0.33 mg/mouse; KO-NEB, n=5). Treatments were administered once a week starting at 8 weeks of age and the heart was harvested 12 weeks post-ERT. Mouse heart samples were prepared for global proteomics measurements with Nano-liquid chromatography tandem mass spectrometry (n=3/group; Nano-LC/MS/MS). Global limma moderated F-test analysis identified 928 differently abundant proteins across the four groups. Pairwise Euclidean distances from the IDS-KO were significantly greater for the KO-NEB vs KO-IV group (47.5, 3.7 vs 40.8, 1.1; p < 0.001), showing that adjunct nebulization elicited a more profound proteomic shift than IV alone. The mean z-score compartment analysis revealed that the subcellular compartment protein profile of KO-NEB shifted towards the WT profile, whereas this pattern was less evident in KO-IV. The cluster analysis also revealed treatment-specific and rescue-like protein modules. Overall, our results suggest that adjunctive nebulized Idursulfase ERT enhances the cardiac proteomic changes caused by IV treatment in IDS-KO mice. Proteomics data are available via ProteomeXchange with identifier PXD083242.
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BibTeX
@misc{mariani2026adjunctive,
title = {{Adjunctive nebulization of Idursulfase to intravenous treatment enhances cardiac proteome adaptations in IDS-KO mice}},
author = {V. M. Mariani and A. Labilloy and W. T. Cade and P. R. Ferreira and L. F. Ferreira},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.07.749889},
url = {https://www.biorxiv.org/content/10.64898/2026.09.07.749889v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Adjunctive nebulization of Idursulfase to intravenous treatment enhances cardiac proteome adaptations in IDS-KO mice
AU - V. M. Mariani
AU - A. Labilloy
AU - W. T. Cade
AU - P. R. Ferreira
AU - L. F. Ferreira
PY - 2026
DA - 2026/09/07
PB - bioRxiv
DO - 10.64898/2026.09.07.749889
UR - https://www.biorxiv.org/content/10.64898/2026.09.07.749889v1
AB - Mucopolysaccharidosis Type II (MPS-II) is a rare X-linked lysosomal storage disorder, characterized by deficiency of the lysosomal hydrolase iduronate 2-sulphatase (IDS). Cardiac impairments contribute to mortality in patients. Enzyme replacement therapy (ERT) with Idursulfase is a promising treatment for the cardiac dysfunction. We compared the proteome changes following intravenous (IV) with and without adjunct nebulized ERT in IDS-KO mice. Male mice were assigned to 4 groups: 1) WT IV + nebulized saline (WT; n=8); 2) IDS-KO IV + nebulized saline (KO; n=5); 3) IDS-KO IV Idursulfase (1 mg/kg; KO-IV, n=5); 4) IDS-KO IV (1 mg/kg) + nebulized Idursulfase (0.33 mg/mouse; KO-NEB, n=5). Treatments were administered once a week starting at 8 weeks of age and the heart was harvested 12 weeks post-ERT. Mouse heart samples were prepared for global proteomics measurements with Nano-liquid chromatography tandem mass spectrometry (n=3/group; Nano-LC/MS/MS). Global limma moderated F-test analysis identified 928 differently abundant proteins across the four groups. Pairwise Euclidean distances from the IDS-KO were significantly greater for the KO-NEB vs KO-IV group (47.5, 3.7 vs 40.8, 1.1; p < 0.001), showing that adjunct nebulization elicited a more profound proteomic shift than IV alone. The mean z-score compartment analysis revealed that the subcellular compartment protein profile of KO-NEB shifted towards the WT profile, whereas this pattern was less evident in KO-IV. The cluster analysis also revealed treatment-specific and rescue-like protein modules. Overall, our results suggest that adjunctive nebulized Idursulfase ERT enhances the cardiac proteomic changes caused by IV treatment in IDS-KO mice. Proteomics data are available via ProteomeXchange with identifier PXD083242.
ER -