Enzyme replacement therapy for mucopolysaccharidoses; past, present, and future

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Abstract

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders, which lack an enzyme corresponding to the specific type of MPS. Enzyme replacement therapy (ERT) has been the standard therapeutic option for some types of MPS because of the ability to start immediate treatment with feasibility and safety and to improve prognosis. There are several disadvantages for current ERT, such as limited impact to the brain and avascular cartilage, weekly or biweekly infusions lasting 4–5 h, the immune response against the infused enzyme, a short half-life, and the high cost. Clinical studies of ERT have shown limited efficacy in preventing or resolving progression in neurological, cardiovascular, and skeletal diseases. One focus is to penetrate the avascular cartilage area to at least stabilize, if not reverse, musculoskeletal diseases. Although early intervention in some types of MPS has shown improvements in the severity of skeletal dysplasia and stunted growth, this limits the desired effect of ameliorating musculoskeletal disease progression to young MPS patients. Novel ERT strategies are under development to reach the brain: (1) utilizing a fusion protein with monoclonal antibody to target a receptor on the BBB, (2) using a protein complex from plant lectin, glycan, or insulin-like growth factor 2, and (3) direct infusion across the BBB. As for MPS IVA and VI, bone-targeting ERT will be an alternative to improve therapeutic efficacy in bone and cartilage. This review summarizes the effect and limitations on current ERT for MPS and describes the new technology to overcome the obstacles of conventional ERT.

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Acknowledgements

This work was supported by grants from The Carol Ann Foundation, Angelo R. Cali & Mary V. Cali Family Foundation, Inc., The Vain and Harry Fish Foundation, Inc., The Bennett Foundation, Jacob Randall Foundation, Austrian and Japanese MPS societies, and Nemours Funds. This work was supported by the project for baby and infant in research of health and development to Adolescent and young adult from Japan Agency for Medical Research and development, AMED, under grant number JP18gk0110017. RWM and ST were supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of National Institutes of Health (NIH) under grant number P30GM114736. The content of the article has not been influenced by the sponsors.

Author information

HHC is the primary author of this article and has contributed to the concept, planning, data analysis, and reporting of the work described. KS is an expert in pharmacokinetics. He has 10 years of research experience in model mice for translational research and drug development. He has contributed to the editing, data analysis, and reporting of the work described. RWM has contributed to the concept and planning of the project, the draft of the manuscript, and reporting of the work described. HK has contributed to the concept and planning of the project, interpretation of GAG data, and reporting of the work described. SY has contributed to the concept and planning of the project, interpretation of GAG data, and reporting of the work described. YS has contributed to the concept and planning of the project, interpretation of clinical data, and reporting of the work described. TO has contributed to the concept and planning of the project, interpretation of clinical pictures, and GAG data, interpretation of published data and reporting of the work described. ST is a Principal Investigator for this project and has 30 years of clinical and research experience in Morquio A, publishing over 70 articles in this field. He has contributed to the concept, planning, interpretation of published data, and reporting of the work described.

Correspondence to Shunji Tomatsu.

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HHC, KS, RWM, HK, SY, YS, TO, and ST contributed to the Review Article and had no conflict of interest with any other party. All authors declare that they have no conflict of interests.

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