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Putative Biological Mechanisms of Efficiency of Substrate Reduction Therapies for Mucopolysaccharidoses

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Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

Mucopolysaccharidoses (MPS) are inherited metabolic diseases caused by mutations in genes coding for lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). Dysfunction of any of these enzymes results in the accumulation of GAGs, which leads to severe clinical symptoms and significantly shortened life span. Several kinds of therapies have been proposed to treat MPS, including bone marrow or stem cell transplantation, enzyme replacement therapy, and gene therapy. Another option is substrate reduction therapy (SRT), in which synthesis of GAGs is inhibited. Recent studies employing in vitro and animal models suggested that this therapy may be efficient in decreasing levels of GAGs in MPS cells, including those bearing two null alleles of the affected gene. Results of behavioral tests in animals as well as some preliminary clinical observations with pediatric patients corroborated the suggestions about possible efficacy of SRT in MPS treatment, including brain functions. Efficient reduction of GAG levels in MPS cells homozygous for null mutations may be intriguing in the commonly accepted scheme of SRT mode of action. In this paper, we propose an explanation of this phenomenon, based on already known facts. Thus, we suggest that SRT may lead to reduction of GAG levels in MPS cells due to inhibition of efficiency of GAG synthesis combined with (a) any readthrough of the stop codon, (b) dilution of already accumulated GAGs due to cell growth followed by cell divisions, and (c) action of endoglycosidases degrading GAGs, e.g., heparanase, in combination with functional GAG-specific hydrolases.

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Acknowledgments

This work was supported by Ministry of Sciences and Higher Education of Poland (Project Grant No. N N301 668540 to GW), and was operated within the Foundation for Polish Science Team Programme co-financed by the EU European Regional Development Fund (Grant No. TEAM/2008-2/7 to GW).

Conflict of interest

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Neurology, Medical University of Gdańsk, Dębinki 7, 80-211, Gdańsk, Poland

    Zyta Banecka-Majkutewicz

  2. Department of Molecular Biology, University of Gdańsk, Kładki 24, 80-822, Gdańsk, Poland

    Joanna Jakóbkiewicz-Banecka & Grzegorz Węgrzyn

  3. Laboratory of Molecular Biology (Affiliated with the University of Gdańsk), Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Kładki 24, 80-822, Gdańsk, Poland

    Magdalena Gabig-Cimińska

  4. Department of Microbiology, University of Szczecin, Felczaka 3c, 71-412, Szczecin, Poland

    Alicja Węgrzyn

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  1. Zyta Banecka-Majkutewicz
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  2. Joanna Jakóbkiewicz-Banecka
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Correspondence to Zyta Banecka-Majkutewicz.

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Banecka-Majkutewicz, Z., Jakóbkiewicz-Banecka, J., Gabig-Cimińska, M. et al. Putative Biological Mechanisms of Efficiency of Substrate Reduction Therapies for Mucopolysaccharidoses. Arch. Immunol. Ther. Exp. 60, 461–468 (2012). https://doi.org/10.1007/s00005-012-0195-9

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  • DOI: https://doi.org/10.1007/s00005-012-0195-9

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