The Inflammation in the Cytopathology of Patients With Mucopolysaccharidoses- Immunomodulatory Drugs as an Approach to Therapy

doi:10.3389/fphar.2022.863667

Review

. 2022 May 13:13:863667.

doi: 10.3389/fphar.2022.863667. eCollection 2022.

The Inflammation in the Cytopathology of Patients With Mucopolysaccharidoses- Immunomodulatory Drugs as an Approach to Therapy

Anna-Maria Wiesinger^{1

2}, Brian Bigger^{2

3}, Roberto Giugliani⁴, Maurizio Scarpa^{2

5}, Tobias Moser⁶, Christina Lampe^{2

7}, Christoph Kampmann⁸, Florian B Lagler^{1

2}

Affiliations

¹ Institute of Congenital Metabolic Diseases, Paracelsus Medical University, Salzburg, Austria.
² European Reference Network for Hereditary Metabolic Diseases, MetabERN, Udine, Italy.
³ Stem Cell and Neurotherapies, Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
⁴ Department of Genetics, Medical Genetics Service and Biodiscovery Laboratory, HCPA, UFRGS, Porto Alegre, Brazil.
⁵ Regional Coordinating Center for Rare Diseases, University Hospital Udine, Udine, Italy.
⁶ Department of Neurology, Christian Doppler University Hospital, Paracelsus Medical University, Salzburg, Austria.
⁷ Department of Child and Adolescent Medicine, Center of Rare Diseases, University Hospitals Giessen/Marburg, Giessen, Germany.
⁸ Department of Pediatric Cardiology, University Hospital Mainz, Mainz, Germany.

PMID: 35645812
PMCID: PMC9136158
DOI: 10.3389/fphar.2022.863667

Review

The Inflammation in the Cytopathology of Patients With Mucopolysaccharidoses- Immunomodulatory Drugs as an Approach to Therapy

Anna-Maria Wiesinger et al. Front Pharmacol. 2022.

. 2022 May 13:13:863667.

doi: 10.3389/fphar.2022.863667. eCollection 2022.

Authors

Anna-Maria Wiesinger^{1

2}, Brian Bigger^{2

3}, Roberto Giugliani⁴, Maurizio Scarpa^{2

5}, Tobias Moser⁶, Christina Lampe^{2

7}, Christoph Kampmann⁸, Florian B Lagler^{1

2}

Affiliations

¹ Institute of Congenital Metabolic Diseases, Paracelsus Medical University, Salzburg, Austria.
² European Reference Network for Hereditary Metabolic Diseases, MetabERN, Udine, Italy.
³ Stem Cell and Neurotherapies, Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
⁴ Department of Genetics, Medical Genetics Service and Biodiscovery Laboratory, HCPA, UFRGS, Porto Alegre, Brazil.
⁵ Regional Coordinating Center for Rare Diseases, University Hospital Udine, Udine, Italy.
⁶ Department of Neurology, Christian Doppler University Hospital, Paracelsus Medical University, Salzburg, Austria.
⁷ Department of Child and Adolescent Medicine, Center of Rare Diseases, University Hospitals Giessen/Marburg, Giessen, Germany.
⁸ Department of Pediatric Cardiology, University Hospital Mainz, Mainz, Germany.

PMID: 35645812
PMCID: PMC9136158
DOI: 10.3389/fphar.2022.863667

Abstract

Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases (LSDs), characterized by the accumulation of glycosaminoglycans (GAGs). GAG storage-induced inflammatory processes are a driver of cytopathology in MPS and pharmacological immunomodulation can bring improvements in brain, cartilage and bone pathology in rodent models. This manuscript reviews current knowledge with regard to inflammation in MPS patients and provides hypotheses for the therapeutic use of immunomodulators in MPS. Thus, we aim to set the foundation for a rational repurposing of the discussed molecules to minimize the clinical unmet needs still remaining despite enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT).

Keywords: MPS; cytopathology; drug discovery; immunomodulation; inflammation; mucopolysaccharidoses.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

**FIGURE 1**
Inflammatory pathway cue to GAG storage in MPS (orange arrows indicate the process mainly due to HS accumulation, blue arrows indicate processes due to HS, DS, C4S, C6S, KS, and HA accumulation).

**FIGURE 2**
Direct immunomodulatory molecules, which target the cytokine receptor pathway and have already been tested in MPS trials.

**FIGURE 3**
Target points of Abatacept, Alemtuzumab, Anakinra, Adalimumab, and Infliximad. Adaliminab and infliximab block the action of INF-a, Anakinra inhibits the ILI receptor and a following ILI release, Alemtuzumab targets mature B- and T-cells *via* CD52, Abatacept prevents full T-cell activation *via* CD80 and CD86 between antigen presenting cell (APC) and T-cell.

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References

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1. Annunziata I., Sano R., d'Azzo A. (2018). Mitochondria-associated ER Membranes (MAMs) and Lysosomal Storage Diseases. Cell. Death Dis. 9, 328. 10.1038/s41419-017-0025-4 - DOI - PMC - PubMed
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[1] Abdelaziz D. H., Khalil H., Cormet-Boyaka E., Amer A. O. (2015). The Cooperation between the Autophagy Machinery and the Inflammasome to Implement an Appropriate Innate Immune Response: Do They Regulate Each Other? Immunol. Rev. 265, 194–204. 10.1111/imr.12288 - DOI - PMC - PubMed

[2] Abdelaziz D. H., Khalil H., Cormet-Boyaka E., Amer A. O. (2015). The Cooperation between the Autophagy Machinery and the Inflammasome to Implement an Appropriate Innate Immune Response: Do They Regulate Each Other? Immunol. Rev. 265, 194–204. 10.1111/imr.12288 - DOI - PMC - PubMed

[3] Ahmed A., Whitley C. B., Cooksley R., Rudser K., Cagle S., Ali N., et al. (2014). Neurocognitive and Neuropsychiatric Phenotypes Associated with the Mutation L238Q of the α-L-iduronidase Gene in Hurler-Scheie Syndrome. Mol. Genet. Metab. 111, 123–127. 10.1016/j.ymgme.2013.11.014 - DOI - PMC - PubMed

[4] Ahmed A., Whitley C. B., Cooksley R., Rudser K., Cagle S., Ali N., et al. (2014). Neurocognitive and Neuropsychiatric Phenotypes Associated with the Mutation L238Q of the α-L-iduronidase Gene in Hurler-Scheie Syndrome. Mol. Genet. Metab. 111, 123–127. 10.1016/j.ymgme.2013.11.014 - DOI - PMC - PubMed

[5] Alzheimer C., Werner S. (2003). “Fibroblast Growth Factors and Neuroprotection,” in Molecular and Cellular Biology of Neuroprotection in the CNS. Editor Alzheimer C. (Boston, MA: Springer US; ), 335–351. 10.1007/978-1-4615-0123-7_12 - DOI - PubMed

[6] Alzheimer C., Werner S. (2003). “Fibroblast Growth Factors and Neuroprotection,” in Molecular and Cellular Biology of Neuroprotection in the CNS. Editor Alzheimer C. (Boston, MA: Springer US; ), 335–351. 10.1007/978-1-4615-0123-7_12 - DOI - PubMed

[7] Annunziata I., Sano R., d'Azzo A. (2018). Mitochondria-associated ER Membranes (MAMs) and Lysosomal Storage Diseases. Cell. Death Dis. 9, 328. 10.1038/s41419-017-0025-4 - DOI - PMC - PubMed

[8] Annunziata I., Sano R., d'Azzo A. (2018). Mitochondria-associated ER Membranes (MAMs) and Lysosomal Storage Diseases. Cell. Death Dis. 9, 328. 10.1038/s41419-017-0025-4 - DOI - PMC - PubMed

[9] Arfi A., Richard M., Gandolphe C., Bonnefont-Rousselot D., Thérond P., Scherman D. (2011). Neuroinflammatory and Oxidative Stress Phenomena in MPS IIIA Mouse Model: The Positive Effect of Long-Term Aspirin Treatment. Mol. Genet. Metab. 103, 18–25. 10.1016/j.ymgme.2011.01.015 - DOI - PubMed

[10] Arfi A., Richard M., Gandolphe C., Bonnefont-Rousselot D., Thérond P., Scherman D. (2011). Neuroinflammatory and Oxidative Stress Phenomena in MPS IIIA Mouse Model: The Positive Effect of Long-Term Aspirin Treatment. Mol. Genet. Metab. 103, 18–25. 10.1016/j.ymgme.2011.01.015 - DOI - PubMed

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The Inflammation in the Cytopathology of Patients With Mucopolysaccharidoses- Immunomodulatory Drugs as an Approach to Therapy

Affiliations

The Inflammation in the Cytopathology of Patients With Mucopolysaccharidoses- Immunomodulatory Drugs as an Approach to Therapy

Authors

Affiliations

Abstract

Conflict of interest statement

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Abstract

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