Enzyme Replacement Therapy For Mucopolysaccharidosis

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Mucopolysaccharidoses (MPS) is a long, scary word for a rare but severe group of diseases that start at birth. But what does it mean? MPS are a group of diseases, passed on genetically, that affect a person's metabolism; specifically their ability to break down a specific type of carbohydrate called glycosaminoglycans (GAGs).1 GAGs are found throughout the body and are essential building blocks in bone, skin, eyes, and much more.1

GAGs in people suffering from MPS will accumulate throughout the blood, brain, cells, and spinal cord and eventually cause irreversible damage.1 This includes both physical abnormalities and impaired mental function, often leading to death during childhood.1

Enzyme replacement therapy (ERT) has become one of the primary treatment options for MPS: first being licensed in 2003 ERT is now available for five types of MPS.2 This process involves the transfusion of the enzymes the patient with MPS is missing through an IV. The body will then use that enzyme to break down the GAGs and return body levels back to normal.3 Whilst this process is revolutionary and can prolong life in patients, it does have its drawbacks; ERT will not reverse the damage done to cognitive function, hearing loss, or eye or skeletal damage. As such, the most effective implementation of ERT is early on in the progress of disease where damage is minimal.4 ERT can slow the progress of disease making living with the condition far more manageable for the patient.4 In this article we will cover how MPS and ERT work, what ERTs are out there, the challenges of ERT, and the prognosis of patients suffering from MPS.

Understanding mucopolysaccharidosis

As we have covered mucopolysaccharidosis is a genetic disorder where the body cannot correctly break down glycosaminoglycans. This is due to mutations in the enzymes involved in this process; either through them having limited or no functionality, or issues producing the enzyme in high enough quantities.1 But what is an enzyme? Enzymes are proteins produced in your cells, they help facilitate the chemical reactions in your body, including breaking down and creating new structures in every organ and system. In MPS only enzymes affecting the breakdown of GAGs are affected, meaning they build up within the body and cause damage.

Due to the number of enzymes involved in this process, there are many forms of MPS. Here is a list of the subtypes of MPS and the enzymes involved in each.

  • MPS I: caused by a deficiency in α-L-iduronidase. It can be broken down into three further subtypes from most severe to least: Hurler syndrome, Hurler/Scheie syndrome and Scheie syndrome5
  • MPS II: caused by a deficiency in iduronate-2-sulfatase5
  • MPS III: this type has further subtypes; A, B, C, and D with a respective enzyme deficiency in; heparan-N-sulfatase, α-N-acetylglucosaminidase, α-glucosaminidase acetyltransferase, and N-acetylglucosamine-6-sulfatase5
  • MPS IV: can come in two subtypes; A with a deficiency in N-acetylgalactosamine-6-sulfate sulfatase, and B with a deficiency in β-galactosidase
  • MPS VI: is caused by a deficiency in N-acetylgalactosamine-4-sulfatse5
  • MPS VII: is caused by a deficiency in β-glucuronidase5
  • MPS IX: is caused by a deficiency in Hyaluronidase 15

Don’t worry if the names of these enzymes seem complicated: they are! People with MPS will likely only have a deficiency in only one of these enzymes, so only have one to remember. It is very important to know the type of MPS a patient has, as that will determine the symptoms and challenges the patient will face. For instance, patients suffering from MPS I or II can display many symptoms including; skeletal, respiratory, heart, and eye conditions, as well as facial deformities and cognitive difficulties. Whilst those with MPS III display cognitive difficulties, those with MPS IV and VI may have skeletal deformations, those with MPS VII may have extreme fluid buildup, and those with MPS IX may exhibit stunted growth.5

Enzyme replacement therapy basics

Enzyme replacement therapy is the process of treating diseases caused by the deficiency of certain enzymes by reintroducing those enzymes to the body via IV. The enzymes can be human, animal, or made by bacteria.6 The body can then use the new enzymes in lieu of the malfunctioning ones to carry out cellular processes as normal. In terms of MPS, the new enzymes will start to efficiently break down GAGs which restores GAG levels back to baseline.

ERT is not a one time only treatment, and requires a long-term commitment to maintain; infusions for ERT may require several hours each week.2 However, ERT is generally a very safe procedure. The majority of adverse reactions the therapy causes are not severe and easily fixed. The appearance of a rash, nausea, and vomiting are among the common symptoms exhibited but can be mitigated by slowing down the rate of infusion and taking allergy medications such as antihistamines.2

Enzyme replacement therapy: Does it work for MPS?

Sadly, there is no cure for mucopolysaccharidosis, but enzyme replacement therapy can help to slow the progression of the disease and has even been noted, in the case of MPS I, to extend lifespan from 6 years to 9 years.7 The effectiveness of ERT is generally stated to come down to how early the therapy is started, which can translate to a better quality and longer life.As of 2020, there are ERTs for MPS I, II, IVA, VI, and VII, with ERT having a similar effectiveness across the board.2 However, whilst there is a general consensus in the scientific community that ERT can slow the progression of the disease and the development of further symptoms, there is some dispute about reversing symptoms. It is generally agreed upon that ETR can improve pulmonary and respiratory function, as well as improving joint mobility.8

However, due to ERT's inability to cross the blood brain barrier and enter the central nervous system there is no improvement in cognitive impairment, hearing loss, or eye conditions.8 Additionally it seems like ERT struggles to penetrate the bones and cardiac tissue, and as such has little effect on growth and skeletal deformations, as well as heart valve thickening. As It doesn’t reverse a lot of these common symptoms, it is imperative to start ERT as early as possible to slow the onset of these symptoms before they happen.

ERT is perhaps best used in conjunction with the other most popular treatment for MPS: Hematopoietic stem cell transplantation (HSCT).8 This treatment involves the transfusion of healthy donor stem cells into the patient, which go on to produce the necessary enzymes for the body.9 The donor cells can cross the blood-brain barrier and improve cognitive impairment and as such, the pair in combination provides better outcomes for patients across the board.8,9

Challenges and considerations

To provide a full picture surrounding the effectiveness of ERT for the management of MPS we must consider the immune response. When the new enzyme is introduced to the body, the body's immune system will not recognise it as its own and target it, and over time the body will produce antibodies for it.2 This is an issue as it can limit the effectiveness of ERT. The extent of the immune response will depend on the type of mutation in the malfunctioning enzyme; if there is an issue with production and no to little enzyme is produced this response will be great, whilst if there is a mutation in the enzyme itself, and it doesn’t work very well but is still present, the immune response will be small.2

There is much to consider when it comes to ERT; the effectiveness, the progression of MPS, and how intensive the therapy is. It is therefore paramount to have an in-depth, comprehensive discussion with a healthcare professional to choose the best course of action for the child suffering from the condition.

Patient perspectives and quality of life

There is no doubt that mucopolysaccharidosis is one of the scariest diseases to be confronted with; for both the suffering child and the parents. In its most severe forms, MPS can drastically shorten life expectancy and present with symptoms that put a great burden on the child's daily life. Dealing with this disease can be a stressful and bleak time, however, under the guidance of healthcare professionals, the symptoms of the disease can be alleviated bringing a greater quality of life, and much-needed relief to the patient.1 Enzyme replacement therapy (in combination with HSCT) can increase patient mobility and repository function, making moving around easier and increasing stamina.8 A reduction in pain, and when paired with HSCT, improved cognitive abilities and the return of growth may be seen.8

As discussed, ERT is not without its drawbacks. An intensive transfusion process means patients and families must adhere to a strict, long-term schedule. Additionally, depending on where the patient lives, it can be a costly treatment and not accessible to all.8 Whilst ERT is not a cure for MPS, it is still worth considering due to the relief it brings the patients, and its ability to extend the short life expectancy attributed to the disease.


Enzyme replacement therapy is a primary treatment for mucopolysaccharidoses, a group of severe genetic disorders present at birth. GAGs, vital for bodily structures, accumulate in MPS patients, causing irreversible damage. ERT can aid in the breakdown of these molecules by introducing the enzyme missing in the patient, lowering GAG levels, slowing the progression of the disease, and potentially increasing life expectancy. While ERT is revolutionary, it has some limitations including; a significant time and scheduling burden for the patient and limited effectiveness due to issues crossing the blood-brain barrier, issues penetrating bone and heart muscle, and being susceptible to the patient's immune system. However, when paired with HSCT, it can provide a great sense of relief to patients and drastically increase their quality of life.


  • Mucopolysaccharidoses | national institute of neurological disorders and stroke [Internet]. [cited 2024 Jan 8]. Available from: https://www.ninds.nih.gov/health-information/disorders/mucopolysaccharidoses
  • Parini R, Deodato F. Intravenous enzyme replacement therapy in mucopolysaccharidoses: clinical effectiveness and limitations. International Journal of Molecular Sciences [Internet]. 2020 Jan [cited 2024 Jan 8];21(8):2975. Available from: https://www.mdpi.com/1422-0067/21/8/2975
  • Kakkis ED, Muenzer J, Tiller GE, Waber L, Belmont J, Passage M, et al. Enzyme-replacement therapy in mucopolysaccharidosis i. N Engl J Med [Internet]. 2001 Jan 18 [cited 2024 Jan 8];344(3):182–8. Available from: http://www.nejm.org/doi/abs/10.1056/NEJM200101183440304
  • Horovitz DDG, Leão EKEA, Ribeiro EM, Martins AM, Barth AL, Neri JICF, et al. Long-term impact of early initiation of enzyme replacement therapy in 34 MPS VI patients: A resurvey study. Molecular Genetics and Metabolism [Internet]. 2021 May 1 [cited 2024 Jan 8];133(1):94–9. Available from: https://pubmed.ncbi.nlm.nih.gov/33678523/
  • Zhou J, Lin J, Leung WT, Wang L. A basic understanding of mucopolysaccharidosis: Incidence, clinical features, diagnosis, and management. Intractable Rare Dis Res [Internet]. 2020 Feb [cited 2024 Jan 8];9(1):1–9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062595/
  • Enzyme replacement therapy. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012 [cited 2024 Jan 8]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK548796/
  • Solano ML, Fainboim A, Politei J, Porras-Hurtado GL, Martins AM, Souza CFM, et al. Enzyme replacement therapy interruption in patients with Mucopolysaccharidoses: Recommendations for distinct scenarios in Latin America. Molecular Genetics and Metabolism Reports [Internet]. 2020 Jun 1 [cited 2024 Jan 8];23:100572. Available from: https://www.sciencedirect.com/science/article/pii/S2214426920300185
  • Hampe CS, Wesley J, Lund TC, Orchard PJ, Polgreen LE, Eisengart JB, et al. Mucopolysaccharidosis type i: current treatments, limitations, and prospects for improvement. Biomolecules [Internet]. 2021 Jan 29 [cited 2024 Jan 8];11(2):189. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911293/
  • Taylor M, Khan S, Stapleton M, Wang J, Chen J, Wynn R, et al. Hematopoietic stem cell transplantation for mucopolysaccharidoses; past, present, and future. Biol Blood Marrow Transplant [Internet]. 2019 Jul [cited 2024 Jan 8];25(7):e226–46. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615945/

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This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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Elijah Cacicedo-Hough

BS (Biological and Medicinal Chemistry), University of Exeter, United Kingdom

Elijah is a first class graduate from the University of Exeter, with a BSc in Biological and Medicinal Chemistry, earning multiple awards during their studies, including the Deans Award. Having developed a novel ionophore precursor for the sequestration of calcium, Elijah has both laboratory and research experience. With a specific interest in pharmacology, microbiology and disease, Elijah is a passionate medical writer who wants to help make science more accessible to everyone.

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