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

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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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Fig. 1


  1. 1.

    Coutinho MF, Prata MJ, Alves S. Mannose-6-phosphate pathway: a review on its role in lysosomal function and dysfunction. Mol Genet Metab. 2012;105:542–50.

  2. 2.

    Drugs@FDA: FDA approved drug products. accessdata.fda.gov. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020057. Accessed 26 Jul 2019.

  3. 3.

    Shawky RM, Elsayed SM. Treatment options for patients with Gaucher disease. Egypt J Med Hum Genet. 2016;17:281–5.

  4. 4.

    Semenza GL, Pyeritz RE. Respiratory complications of mucopolysaccharide storage disorders. Medicine. 1988;67:209–19.

  5. 5.

    Shih SL, Lee YJ, Lin SP, Sheu CY, Blickman JG. Airway changes in children with mucopolysaccharidoses: CT evaluation. Acta Radiol. 2002;43:40–3.

  6. 6.

    Kenth JJ, Thompson G, Fullwood C, Wilkinson S, Jones S, Bruce IA. The characterisation of pulmonary function in patients with mucopolysaccharidoses IVA: a longitudinal analysis. Mol Genet Metab Rep. 2019;20:100487.

  7. 7.

    Braunlin EA, Harmatz PR, Scarpa M, Furlanetto B, Kampmann C, Loehr JP, et al. Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management. J Inherit Metab Dis 2011;34:1183–97.

  8. 8.

    Kampmann C, Abu-Tair T, Gökce S, Lampe C, Reinke J, Mengel E, et al. Heart and cardiovascular involvement in patients with Mucopolysaccharidosis type IVA (Morquio-a syndrome). PLoS One. 2016;11:e0162612.

  9. 9.

    Extension study evaluating long term safety and activity of AGT-181 in children with MPS I. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03071341. Accessed 26 Jul 2019.

  10. 10.

    A study of JR-141 in patients with mucopolysaccharidosis II. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03568175. Accessed 26 Jul 2019.

  11. 11.

    Safety and dose ranging study of insulin receptor MoAb-IDS fusion protein in patients with hunter syndrome. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02262338?term=NCT02262338&rank=1. Accessed 26 Jul 2019.

  12. 12.

    Boado RJ, Lu JZ, Hui EK, Pardridge WM. Insulin receptor antibody–sulfamidase fusion protein penetrates the primate blood–brain barrier and reduces glycosoaminoglycans in Sanfilippo type A cells. Mol Pharm. 2014;11:2928–34.

  13. 13.

    Boado RJ, Lu JZ, Hui EK, Lin H, Pardridge WM. Insulin receptor antibody− α-N-acetylglucosaminidase fusion protein penetrates the primate blood–brain barrier and reduces Glycosoaminoglycans in Sanfilippo type B fibroblasts. Mol Pharm. 2016;13:1385–92.

  14. 14.

    Intrathecal enzyme replacement therapy for spinal cord compression in mucopolysaccharidosis (MPS) I. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT00215527. Accessed 26 Jul 2019.

  15. 15.

    Study of long term safety and clinical outcomes of idursulfase IT and elaprase treatment in pediatric participants who have completed study HGT-HIT-094. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02412787. Accessed 26 Jul 2019.

  16. 16.

    An extension study to determine safety and efficacy for pediatric patients with MPS type IIIA disease who participated in study HGT-SAN-093. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02350816. Accessed 26 Jul 2019.

  17. 17.

    A treatment study of mucopolysaccharidosis type IIIB (MPS IIIB). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02754076. Accessed 26 Jul 2019.

  18. 18.

    Tomatsu S, Montaño AM, Dung VC, Ohashi A, Oikawa H, Oguma T, et al. Enhancement of drug delivery: enzyme-replacement therapy for murine Morquio A syndrome. Mol Ther. 2010;18:1094–102.

  19. 19.

    Clarke LA, Wraith JE, Beck M, Kolodny EH, Pastores GM, Muenzer J, et al. Long-term efficacy and safety of laronidase in the treatment of mucopolysaccharidosis I. Pediatrics. 2009;123:229–40.

  20. 20.

    Sato Y, Fujiwara M, Kobayashi H, Yoshitake M, Hashimoto K, Oto Y, et al. Residual glycosaminoglycan accumulation in mitral and aortic valves of a patient with attenuated MPS I (Scheie syndrome) after 6 years of enzyme replacement therapy: implications for early diagnosis and therapy. Mol Genet Metab Rep. 2015;5:94–7.

  21. 21.

    Biernacka M, Jakubowska-Winecka A, Tylki-Szymańska A. The development of cognitive functions in children with Hurler phenotype mucopolysaccharidosis type I on enzyme replacement therapy with laronidase. Pediatr Endocrinol diabetes Metab. 2010;16:249–54.

  22. 22.

    Dornelles AD, Artigalás O, da Silva AA, Ardila DL, Alegra T, Pereira TV. et al. Efficacy and safety of intravenous laronidase for mucopolysaccharidosis type I: a systematic review and meta-analysis. PLoS One. 2017;12:e0184065

  23. 23.

    Xue Y, Richards SM, Mahmood A, Cox GF. Effect of anti-laronidase antibodies on efficacy and safety of laronidase enzyme replacement therapy for MPS I: a comprehensive meta-analysis of pooled data from multiple studies. Mol Genet Metab. 2016;117:419–26.

  24. 24.

    Różdżyńska-Świątkowska A, Jurecka A, Cieślik J, Tylki-Szymańska A. Growth patterns in children with mucopolysaccharidosis I and II. World J Pediatr. 2015;11:226–31.

  25. 25.

    Souillet G, Guffon N, Maire I, Pujol M, Taylor P, Sevin F, et al. Outcome of 27 patients with Hurler’s syndrome transplanted from either related or unrelated haematopoietic stem cell sources. Bone Marrow Transplant. 2003;31:1105.

  26. 26.

    Ou L, Herzog T, Koniar BL, Gunther R, Whitley CB. High-dose enzyme replacement therapy in murine Hurler syndrome. Mol Genet Metab. 2014;111:116–22.

  27. 27.

    Muenzer J, Wraith JE, Beck M, Giugliani R, Harmatz P, Eng CM, et al. A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome). Genet Med. 2006;8:465.

  28. 28.

    Da Silva EM, Strufaldi MW, Andriolo RB, Silva LA. Enzyme replacement therapy with idursulfase for mucopolysaccharidosis type II (Hunter syndrome). Cochrane Database of Syst Rev. 2016;2:CD008185. https://doi.org/10.1002/14651858.CD008185.pub4.

  29. 29.

    Whiteman DA, Kimura A. Development of idursulfase therapy for mucopolysaccharidosis type II (Hunter syndrome): the past, the present and the future. Drug Des Dev Ther. 2017;11:2467.

  30. 30.

    Kim C, Seo J, Chung Y, Ji HJ, Lee J, Sohn J, et al. Comparative study of idursulfase beta and idursulfase in vitro and in vivo. J Hum Genet. 2017;62:167.

  31. 31.

    Sohn YB, Cho SY, Lee J, Kwun Y, Huh R, Jin DK. Safety and efficacy of enzyme replacement therapy with idursulfase beta in children aged younger than 6 years with Hunter syndrome. Mol Genet Metab. 2015;114:156–60.

  32. 32.

    Sohn YB, Cho SY, Park SW, Kim SJ, Ko AR, Kwon EK, et al. Phase I/II clinical trial of enzyme replacement therapy with idursulfase beta in patients with mucopolysaccharidosis II (Hunter syndrome). Orphanet J Rare Dis. 2013;8:42.

  33. 33.

    Parini R, Jones SA, Harmatz PR, Giugliani R, Mendelsohn NJ. The natural history of growth in patients with Hunter syndrome: data from the Hunter Outcome Survey (HOS). Mol Genet Metab. 2016;117:438–46.

  34. 34.

    Parini R, Rigoldi M, Tedesco L, Boffi L, Brambilla A, Bertoletti S, et al. Enzymatic replacement therapy for Hunter disease: up to 9 years experience with 17 patients. Mol Genet Metab Rep. 2015;3:65–74.

  35. 35.

    Jones SA, Parini R, Harmatz P, Giugliani R, Fang J, Mendelsohn NJ, et al. The effect of idursulfase on growth in patients with Hunter syndrome: data from the Hunter Outcome Survey (HOS). Mol Genet Metab. 2013;109:41–8.

  36. 36.

    Schulze‐Frenking G, Jones SA, Roberts J, Beck M, Wraith JE. Effects of enzyme replacement therapy on growth in patients with mucopolysaccharidosis type II. J Inherit Metab Dis. 2011;34:203–8.

  37. 37.

    Glamuzina E, Fettes E, Bainbridge K, Crook V, Finnegan N, Abulhoul L, et al. Treatment of mucopolysaccharidosis type II (Hunter syndrome) with idursulfase: the relevance of clinical trial end points. J Inherit Metab Dis. 2011;34:749–54.

  38. 38.

    Muenzer J, Giugliani R, Scarpa M, Tylki-Szymańska A, Jego V, Beck M. Clinical outcomes in idursulfase-treated patients with mucopolysaccharidosis type II: 3-year data from the hunter outcome survey (HOS). Orphanet J Rare Dis. 2017;12:161.

  39. 39.

    Kim S, Whitley CB, Utz JR. Correlation between urinary GAG and anti-idursulfase ERT neutralizing antibodies during treatment with NICIT immune tolerance regimen: a case report. Mol Genet Metab. 2017;122:92–9.

  40. 40.

    Giugliani R, Harmatz P, Jones SA, Mendelsohn NJ, Vellodi A, Qiu Y, et al. Evaluation of impact of anti-idursulfase antibodies during long-term idursulfase enzyme replacement therapy in mucopolysaccharidosis II patients. Mol Genet Metab Rep. 2017;12:2–7.

  41. 41.

    Pano A, Barbier AJ, Bielefeld B, Whiteman DA, Amato DA. Immunogenicity of idursulfase and clinical outcomes in very young patients (16 months to 7.5 years) with mucopolysaccharidosis II (Hunter syndrome). Orphanet J Rare Dis. 2015;10:50.

  42. 42.

    Kubaski F, Yabe H, Suzuki Y, Seto T, Hamazaki T, Mason RW, et al. Hematopoietic stem cell transplantation for patients with mucopolysaccharidosis II. Biol Blood Marrow Transplant. 2017;23:1795–803.

  43. 43.

    Safety, pharmacokinetics, and pharmacodynamics/efficacy of SBC-103 in mucopolysaccharidosis III, type B (MPS IIIB). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02324049. Accessed 26 Jul 2019.

  44. 44.

    Alexion presents new SBC-103 (rhNAGLU enzyme) phase 1/2 data on brain MRI and neurocognitive assessments in patients with mucopolysaccharidosis IIIB (MPS IIIB) | Alexion Pharmaceuticals, Inc. http://news.alexionpharma.com/press-release/product-news/alexion-presents-new-sbc-103-rhnaglu-enzyme-phase-12-data-brain-mri-and-n. Accessed 26 Jul 2019.

  45. 45.

    Alexion reports fourth quarter and full year 2016 results and provides financial guidance for 2017 | Alexion Pharmaceuticals, Inc. http://news.alexionpharma.com/press-release/financial-news/alexion-reports-fourth-quarter-and-full-year-2016-results-and-provides-. Accessed 26 Jul 2019.

  46. 46.

    Lin HY, Chuang CK, Ke YY, Hsu CC, Chiu PC, Niu DM, et al. Long-term effects of enzyme replacement therapy for Taiwanese patients with mucopolysaccharidosis IVA. Pediatr Neonatol. 2019;60:342–3.

  47. 47.

    Hughes D, Giugliani R, Guffon N, Jones SA, Mengel KE, Parini R, et al. Clinical outcomes in a subpopulation of adults with Morquio A syndrome: results from a long-term extension study of elosulfase alfa. Orphanet J Rare Dis. 2017;12:98.

  48. 48.

    Harmatz PR, Mengel E, Geberhiwot T, Muschol N, Hendriksz CJ, Burton BK, et al. Impact of elosulfase alfa in patients with morquio A syndrome who have limited ambulation: an open‐label, phase 2 study. Am J Med Genet Part A. 2017;173:375–83.

  49. 49.

    Hendriksz CJ, Giugliani R, Harmatz P, Mengel E, Guffon N, Valayannopoulos V, et al. Multi-domain impact of elosulfase alfa in Morquio A syndrome in the pivotal phase III trial. Mol Genet Metab. 2015;114:178–85.

  50. 50.

    Do Cao J, Wiedemann A, Quinaux T, Battaglia-Hsu SF, Mainard L, Froissart R, et al. 30 months follow-up of an early enzyme replacement therapy in a severe Morquio A patient: about one case. Mol Genet Metab Rep. 2016;9:42–5.

  51. 51.

    Pintos-Morell G, Blasco-Alonso J, Couce ML, Gutiérrez-Solana LG, Guillén-Navarro E, O’Callaghan M, et al. Elosulfase alfa for mucopolysaccharidosis type IVA: real-world experience in 7 patients from the Spanish Morquio-A early access program. Mol Genet Metab Rep. 2018;15:116–20.

  52. 52.

    Khan SA, Mason RW, Giugliani R, Orii K, Fukao T, Suzuki Y, et al. Glycosaminoglycans analysis in blood and urine of patients with mucopolysaccharidosis. Mol Genet Metab. 2018;125:44–52.

  53. 53.

    Long B, Tompkins T, Decker C, Jesaitis L, Khan S, Slasor P, et al. Long-term immunogenicity of elosulfase alfa in the treatment of Morquio A syndrome: results from MOR-005, a phase III extension study. Clin Ther. 2017;39:118–29.

  54. 54.

    Tomatsu S, Averill LW, Sawamoto K, Mackenzie WG, Bober MB, Pizarro C, et al. Obstructive airway in Morquio A syndrome, the past, the present and the future. Mol Genet Metab. 2016;117:150–6.

  55. 55.

    Tomatsu S, Sawamoto K, Shimada T, Bober MB, Kubaski F, Yasuda E, et al. Enzyme replacement therapy for treating mucopolysaccharidosis type IVA (Morquio A syndrome): effect and limitations. Expert Opin Orphan Drugs. 2015;3:1279–90.

  56. 56.

    Tomatsu S, Sawamoto K, Alméciga-Díaz CJ, Shimada T, Bober MB, Chinen Y, et al. Impact of enzyme replacement therapy and hematopoietic stem cell transplantation in patients with Morquio A syndrome. Drug Des Dev Ther. 2015;9:1937.

  57. 57.

    Tomatsu S, Alméciga-Díaz CJ, Montaño AM, Yabe H, Tanaka A, Dung VC, et al. Therapies for the bone in mucopolysaccharidoses. Mol Genet Metab. 2015;114:94–109.

  58. 58.

    Tomatsu S, Montaño AM, Ohashi A, Gutierrez MA, Oikawa H, Oguma T, et al. Enzyme replacement therapy in a murine model of Morquio A syndrome. Hum Mol Genet. 2007;17:815–24.

  59. 59.

    Sawamoto K, Suzuki Y, Mackenzie WG, Theroux MC, Pizarro C, Yabe H, et al. Current therapies for Morquio A syndrome and their clinical outcomes. Expert Opin Orphan Drugs. 2016;4:941–51.

  60. 60.

    Jones SA, Bialer M, Parini R, Martin K, Wang H, Yang K, et al. Safety and clinical activity of elosulfase alfa in pediatric patients with Morquio A syndrome (mucopolysaccharidosis IVA) less than 5 y. Pediatr Res. 2015;78:717.

  61. 61.

    Concolino D, Deodato F, Parini R. Enzyme replacement therapy: efficacy and limitations. Ital J Pediatr. 2018;44:120.

  62. 62.

    Doherty C, Stapleton M, Piechnik M, Mason RW, Mackenzie WG, Yamaguchi S. Effect of enzyme replacement therapy on the growth of patients with Morquio A. J Hum Genet. 2019;64:625.

  63. 63.

    Glössl J, Kresse H. Impaired degradation of keratan sulphate by Morquio A fibroblasts. Biochem J. 1982;203:335–8.

  64. 64.

    Anderson CE, Crane JT, Harper HA, Hunter TW. Morquio’s disease and dysplasia epiphysalis multiplex: a study of epiphyseal cartilage in seven cases. J Bone Joint Surg. 1962;44:295–306.

  65. 65.

    Zustin J. Morquio disease: the role of cartilage canals in the pathogenesis of chondrogenic dwarfism. Med Hypotheses. 2010;75:642–4.

  66. 66.

    Donida B, Marchetti DP, Biancini GB, Deon M, Manini PR, da Rosa HT, et al. Oxidative stress and inflammation in mucopolysaccharidosis type IVA patients treated with enzyme replacement therapy. Biochim Biophys Acta. 2015;1852:1012–9.

  67. 67.

    Giugliani R, Lampe C, Guffon N, Ketteridge D, Leão‐Teles E, Wraith JE, et al. Natural history and galsulfase treatment in mucopolysaccharidosis VI (MPS VI, Maroteaux–Lamy syndrome)—10‐year follow‐up of patients who previously participated in an MPS VI survey study. Am J Med Genet Part A. 2014;164:1953–64.

  68. 68.

    Harmatz P, Giugliani R, Schwartz I, Guffon N, Teles EL, Miranda MC, et al. Enzyme replacement therapy for mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (recombinant human arylsulfatase B or rhASB) and follow-on, open-label extension study. J Pediatr. 2006;148:533–9.

  69. 69.

    Harmatz P, Yu ZF, Giugliani R, Schwartz IV, Guffon N, Teles EL, et al. Enzyme replacement therapy for mucopolysaccharidosis VI: evaluation of long‐term pulmonary function in patients treated with recombinant human N‐acetylgalactosamine 4‐sulfatase. J Inherit Metab Dis. 2010;33:51–60.

  70. 70.

    Quartel A, Harmatz PR, Lampe C, Guffon N, Ketteridge D, Leão-Teles E, et al. Long-term galsulfase treatment associated with improved survival of patients with mucopolysaccharidosis VI (Maroteaux-Lamy Syndrome) 15-year follow-up from the survey study. J Inborn Errors Metab Screen. 2018;6:2326409818755800.

  71. 71.

    McGill JJ, Inwood AC, Coman DJ, Lipke ML, De Lore D, Swiedler SJ, et al. Enzyme replacement therapy for mucopolysaccharidosis VI from 8 weeks of age–a sibling control study. Clin Genet. 2010;77:492–8.

  72. 72.

    Kılıç M, Dursun A, Coşkun T, Tokatlı A, Özgül RK, Yücel‐Yılmaz D, et al. Genotypic‐phenotypic features and enzyme replacement therapy outcome in patients with mucopolysaccharidosis VI from Turkey. Am J Med Genet Part A. 2017;173:2954–67.

  73. 73.

    Kampmann C, Lampe C, Whybra-Trümpler C, Wiethoff CM, Mengel E, Arash L, et al. Mucopolysaccharidosis VI: cardiac involvement and the impact of enzyme replacement therapy. J Inherit Metab Dis. 2014;37:269–76.

  74. 74.

    Furujo M, Kubo T, Kosuga M, Okuyama T. Enzyme replacement therapy attenuates disease progression in two Japanese siblings with mucopolysaccharidosis type VI. Mol Genet Metab. 2011;104:597–602.

  75. 75.

    Furujo M, Kosuga M, Okuyama T. Enzyme replacement therapy attenuates disease progression in two Japanese siblings with mucopolysaccharidosis type VI: 10-year follow up. Mol Genet Metab Rep. 2017;13:69–75.

  76. 76.

    Quartel A, Hendriksz CJ, Parini R, Graham S, Lin P, Harmatz P. Growth charts for individuals with mucopolysaccharidosis vi (maroteaux–lamy syndrome). InJIMD Reports, volume 18. Berlin, Heidelberg: Springer; 2014. p. 1–11.

  77. 77.

    Horovitz DD, Magalhães TS, Acosta A, Ribeiro EM, Giuliani LR, Palhares DB, et al. Enzyme replacement therapy with galsulfase in 34 children younger than five years of age with MPS VI. Mol Genet Metab. 2013;109:62–9.

  78. 78.

    Lourenço CM, Giugliani R. Evaluation of galsulfase for the treatment of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Expert Opin Orphan Drugs. 2014;2:407–17.

  79. 79.

    Brands MM, Hoogeveen-Westerveld M, Kroos MA, Nobel W, Ruijter GJ, Özkan L, et al. Mucopolysaccharidosis type VI phenotypes-genotypes and antibody response to galsulfase. Orphanet J Rare Dis. 2013;8:51.

  80. 80.

    Brooks DA, King BM, Crawley AC, Byers S, Hopwood JJ. Enzyme replacement therapy in mucopolysaccharidosis VI: evidence for immune responses and altered efficacy of treatment in animal models. Biochim Biophys Acta. 1997;1361:203–16.

  81. 81.

    McCafferty EH, Scott LJ. Vestronidase alfa: a review in mucopolysaccharidosis VII. BioDrugs. 2019;33:233–40.

  82. 82.

    Bigg PW, Baldo G, Sleeper MM, O’Donnell PA, Bai H, Rokkam VR, et al. Pathogenesis of mitral valve disease in mucopolysaccharidosis VII dogs. Mol Genet Metab. 2013;110:319–28.

  83. 83.

    Grubb JH, Vogler C, Levy B, Galvin N, Tan Y, Sly WS. Chemically modified β-glucuronidase crosses blood–brain barrier and clears neuronal storage in murine mucopolysaccharidosis VII. Proc Natl Acad Sci USA. 2008;105:2616–21.

  84. 84.

    Montaño AM, Oikawa H, Tomatsu S, Nishioka T, Vogler C, Gutierrez MA, et al. Acidic amino acid tag enhances response to enzyme replacement in mucopolysaccharidosis type VII mice. Mol Genet Metab. 2008;94:178–89.

  85. 85.

    Harmatz P, Whitley CB, Wang RY, Bauer M, Song W, Haller C, et al. A novel blind start study design to investigate vestronidase alfa for mucopolysaccharidosis VII, an ultra-rare genetic disease. Mol Genet Metab. 2018;123:488–94.

  86. 86.

    Wang R, da Silva Franco JF, Harmatz P, López-Valdez J, Martins E, Sutton VR, et al. Sustained efficacy and safety of vestronidase alfa (rhGUS) enzyme replacement therapy in patients with MPS VII. Mol Genet Metab. 2018;123:S144–5.

  87. 87.

    Lau HA, Parmar S, Kazachkov M, Shah R, Wells J, Yachelevich N, et al. Enzyme replacement therapy with investigational rhGUS in an infant with non-immune hydrops fetalis and mucopolysaccharidosis type VII. Mol Genet Metab. 2016;2:S71.

  88. 88.

    Kampmann C, Wiethoff CM, Huth RG, Staatz G, Mengel E, Beck M, et al. Management of life-threatening tracheal stenosis and tracheomalacia in patients with mucopolysaccharidoses. InJIMD reports, volume 33. Berlin, Heidelberg: Springer; 2016. p. 33–39.

  89. 89.

    Pizarro C, Davies RR, Theroux M, Spurrier EA, Averill LW, Tomatsu S. Surgical reconstruction for severe tracheal obstruction in Morquio A syndrome. Ann Thorac Surg. 2016;102:e329–31.

  90. 90.

    Giugliani R, Dalla Corte A, Poswar F, Vanzella C, Horovitz D, Riegel M, et al. Intrathecal/Intracerebroventricular enzyme replacement therapy for the mucopolysaccharidoses: efficacy, safety, and prospects. Expert Opin Orphan Drugs. 2018;6:403–11.

  91. 91.

    Boado RJ, Zhang Y, Zhang Y, Xia CF, Wang Y, Pardridge WM. Genetic engineering of a lysosomal enzyme fusion protein for targeted delivery across the human blood‐brain barrier. Biotechnol Bioeng. 2008;99:475–84.

  92. 92.

    Boado RJ, Pardridge WM. Brain and organ uptake in the rhesus monkey in vivo of recombinant iduronidase compared to an insulin receptor antibody–iduronidase fusion protein. Mol Pharm. 2017;14:1271–7.

  93. 93.

    Safety and dose ranging study of human insulin receptor MAb-IDUA fusion protein in adults and children with MPS I. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03053089. Accessed 26 Jul 2019.

  94. 94.

    Pardridge WM, Boado RJ, Giugliani R, Schmidt M. Plasma pharmacokinetics of valanafusp alpha, a human insulin receptor antibody-iduronidase fusion protein, in patients with mucopolysaccharidosis type I. BioDrugs. 2018;32:169–76.

  95. 95.

    Schmidt M, Boado RJ, Giugliani R, Pardridge WM. Anti-drug antibody response in mucopolysaccharidosis type I patients treated with AGT-181, a brain penetrating human insulin receptor antibody-iduronidase fusion protein. Mol Genet Metab. 2018;123:S126.

  96. 96.

    Giugliani R, Giugliani L, de Oliveira Poswar F, Donis KC, Dalla Corte A, Schmidt M, et al. Neurocognitive and somatic stabilization in pediatric patients with severe mucopolysaccharidosis type i after 52 weeks of intravenous brain-penetrating insulin receptor antibody-iduronidase fusion protein (valanafusp alpha): an open label phase 1–2 trial. Orphanet J Rare Dis. 2018;13:110.

  97. 97.

    Boado RJ, Lu JZ, Hui EK, Lin H, Pardridge WM. Insulin receptor antibody− α-N-acetylglucosaminidase fusion protein penetrates the primate blood–brain barrier and reduces glycosoaminoglycans in sanfilippo type B fibroblasts. Mol Pharm. 2016;13:1385–92.

  98. 98.

    Sonoda H, Morimoto H, Yoden E, Koshimura Y, Kinoshita M, Golovina G, et al. A blood-brain-barrier-penetrating anti-human transferrin receptor antibody fusion protein for neuronopathic mucopolysaccharidosis II. Mol Ther. 2018;26:1366–74.

  99. 99.

    A study of JR-141 in patients with mucopolysaccharidosis II. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03359213. Accessed 26 Jul 2019.

  100. 100.

    Okuyama T, Eto Y, Sakai N, Minami K, Yamamoto T, Sonoda H, et al. Iduronate-2-sulfatase with anti-human transferrin receptor antibody for neuropathic mucopolysaccharidosis II: a phase 1/2 trial. Mol Ther. 2019;27:456–64.

  101. 101.

    Acosta W, Ayala J, Dolan MC, Cramer CL. RTB Lectin: a novel receptor-independent delivery system for lysosomal enzyme replacement therapies. Sci Rep. 2015;5:14144.

  102. 102.

    Ou L, Acosta W, Koniar BL, Cooksley RD, Cramer CL, Radin DN, et al. Enzyme replacement therapy with α-L-iduronidase and lectin RTB fusion protein in treating murine Hurler syndrome. Mol Genet Metab. 2016;2:S88.

  103. 103.

    Ou L, Przybilla MJ, Koniar B, Whitley CB. RTB lectin-mediated delivery of lysosomal α-l-iduronidase mitigates disease manifestations systemically including the central nervous system. Mol Genet Metab. 2018;123:105–11.

  104. 104.

    Condori J, Katta V, Acosta W, Ayala J, Flory A, Radin J, et al. Novel bioproduction and delivery strategies for MPS IIIA enzyme replacement therapeutics. Mol Genet Metab. 2016;2:S36.

  105. 105.

    A study to assess the safety and tolerability of SOBI003 in pediatric MPS IIIA patients. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03423186. Accessed 26 Jul 2019.

  106. 106.

    Kan SH, Aoyagi-Scharber M, Le SQ, Vincelette J, Ohmi K, Bullens S, et al. Delivery of an enzyme-IGFII fusion protein to the mouse brain is therapeutic for mucopolysaccharidosis type IIIB. Proc Natl Acad Sci USA. 2014;111:14870–5.

  107. 107.

    Kan SH, Troitskaya LA, Sinow CS, Haitz K, Todd AK, Di Stefano A, et al. Insulin-like growth factor II peptide fusion enables uptake and lysosomal delivery of α-N-acetylglucosaminidase to mucopolysaccharidosis type IIIB fibroblasts. Biochem J. 2014;458:281–9.

  108. 108.

    Tong PY, Tollefsen SE, Kornfeld. The cation-independent mannose 6-phosphate receptor binds insulin-like growth factor II. J Biol Chem. 1988;263:2585–8.

  109. 109.

    A treatment extension study of mucopolysaccharidosis type IIIB. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03784287. Accessed 26 Jul 2019.

  110. 110.

    BMN-250 shows promise as effective treatment for sanfilippo type B. Sanfilippo syndrome news. 2019. https://sanfilipponews.com/2019/02/14/bmn-250-shows-promise-treatment-sanfilippo-type-b/. Accessed 26 Jul 2019.

  111. 111.

    Byrne BJ, Geberhiwot T, Barshop BA, Barohn R, Hughes D, Bratkovic D, et al. A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease. Orphanet J Rare Dis. 2017;12:144.

  112. 112.

    Aoyagi-Scharber M, Crippen-Harmon D, Lawrence R, Vincelette J, Yogalingam G, Prill H, et al. Clearance of heparan sulfate and attenuation of CNS pathology by intracerebroventricular BMN 250 in Sanfilippo type B mice. Mol Ther Methods Clin Dev. 2017;6:43–53.

  113. 113.

    Yogalingam G, Luu AR, Prill H, Lo MJ, Yip B, Holtzinger J, et al. BMN 250, a fusion of lysosomal alpha-N-acetylglucosaminidase with IGF2, exhibits different patterns of cellular uptake into critical cell types of Sanfilippo syndrome B disease pathogenesis. PLoS One. 2019;14:e0207836.

  114. 114.

    Cleary M, Muschol N, Couce ML, Harmatz P, Lee J, Lin SP, et al. ICV-administered tralesinidase alfa (BMN 250 NAGLU-IGF2) is well-tolerated and reduces heparan sulfate accumulation in the CNS of subjects with Sanfilippo syndrome type B (MPS IIIB). Mol Genet Metab. 2019;126:S40.

  115. 115.

    Salvalaio M, Rigon L, Belletti D, D’Avanzo F, Pederzoli F, Ruozi B, et al. Targeted polymeric nanoparticles for brain delivery of high molecular weight molecules in lysosomal storage disorders. PLoS One. 2016;11:e0156452.

  116. 116.

    Fujisaki J, Tokunaga Y, Takahashi T, Shimojo F, Kimura S, Hata T. Osteotropic drug delivery system (ODDS) based on bisphosphonic prodrug. I.v. effects of osteotropic estradiol on bone mineral density and uterine weight in ovariectomized rats. J Drug Target. 1998;5:129–38.

  117. 117.

    Kasugai S, Fujisawa R, Waki Y, Miyamoto K, Ohya K. Selective drug delivery system to bone: small peptide (Asp)6 conjugation. J Bone Min Res. 2000;15:936–43.

  118. 118.

    Appel MJ, Bertozzi CR. Formylglycine, a post-translationally generated residue with unique catalytic capabilities and biotechnology applications. ACS Chem Biol. 2014;10:72–84.

  119. 119.

    Tomatsu S, Montaño AM, Oikawa H, Dung VC, Hashimoto A, Oguma T, et al. Enzyme replacement therapy in newborn mucopolysaccharidosis IVA mice: early treatment rescues bone lesions? Mol Genet Metab. 2015;114:195–202.

  120. 120.

    A study of intrathecal enzyme therapy for cognitive decline in MPS I. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT00852358. Accessed 26 Jul 2019.

  121. 121.

    Extension study of intrathecal enzyme replacement for cognitive decline in MPS I. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02232477. Accessed 26 Jul 2019.

  122. 122.

    Study of intrathecal idursulfase-IT administered in conjunction with Elaprase® in pediatric patients with hunter syndrome and early cognitive impairment (AIM-IT). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02055118. Accessed 26 Jul 2019

  123. 123.

    Muenzer J, Hendriksz CJ, Fan Z, Vijayaraghavan S, Perry V, Santra S, et al. A phase I/II study of intrathecal idursulfase-IT in children with severe mucopolysaccharidosis II. Genet Med. 2016;18:73.

  124. 124.

    Shire announces top-line results for phase II/III clinical trial in children with hunter syndrome and cognitive impairment. Shire.com. 2019. https://www.shire.com/en/newsroom/2017/december/wvdwq3. Accessed 26 Jul 2019.

  125. 125.

    Shire reports Q3 2016 results with record revenues and reiterates full year Non GAAP guidance. Shire.com. 2019. https://www.shire.com/en/newsroom/2016/november/aac63r. Accessed 26 Jul 2019.

  126. 126.

    Randomized, controlled, open-label, multicenter, safety and efficacy study of rhhns administration via an iddd in pediatric patients with early stage MPS IIIA disease. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02060526. Accessed 26 Jul 2019.

  127. 127.

    Jones SA, Breen C, Heap F, Rust S, de Ruijter J, Tump E, et al. A phase 1/2 study of intrathecal heparan-N-sulfatase in patients with mucopolysaccharidosis IIIA. Mol Genet Metab. 2016;118:198–205.

  128. 128.

    Phase 1/2 trial of green cross’ idursulfase-beta ICV for the treatment of hunter syndrome with neurocognitive decline—checkorphan. Checkorphan.org. 2019. http://www.checkorphan.org/news/phase-1-2-trial-of-green-cross-idursulfase-beta-icv-for-the-treatment-of-hunter-syndrome-with-neurocognitive-decline#. Accessed 26 Jul 2019.

  129. 129.

    Sohn YB, Ko AR, Seong MR, Lee S, Kim MR, Cho SY, et al. The efficacy of intracerebroventricular idursulfase-beta enzyme replacement therapy in mucopolysaccharidosis II murine model: heparan sulfate in cerebrospinal fluid as a clinical biomarker of neuropathology. J Inherit Metab Dis. 2018;41:1235–46.

  130. 130.

    Sauni CT, Wang F, Kan SH, Le SQ, Anderson B, Wood J, et al. Pilot enzyme replacement therapy with recombinant human glucosamine (N-acetyl)-6-sulfatase in mucopolysaccharidosis type IIID mouse model. Mol Genet Metab. 2018;123:S125.

  131. 131.

    Herskhovitz E, Young E, Rainer J, Hall CM, Lidchi V, Chong K, et al. Bone marrow transplantation for Maroteaux–Lamy syndrome (MPS VI): long-term follow-up. J Inherit Metab Dis. 1999;22:50–62.

  132. 132.

    Vellodi A, Young EP, Cooper A, Wraith JE, Winchester B, Meaney C, et al. Bone marrow transplantation for mucopolysaccharidosis type I: experience of two British centres. Arch Dis Child. 1997;76:92–9.

  133. 133.

    Stem cell transplant w/laronidase for Hurler. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT00176891. Accessed 26 Jul 2019.

  134. 134.

    Tolar J, Grewal SS, Bjoraker KJ, Whitley CB, Shapiro EG, Charnas L, et al. Combination of enzyme replacement and hematopoietic stem cell transplantation as therapy for Hurler syndrome. Bone Marrow Transplant. 2008;41:531.

  135. 135.

    Beck M, Braun S, Coerdt W, Merz E, Young E, Sewell AC. Fetal presentation of Morquio disease type A. Prenat Diagn. 1992;12:1019–29.

  136. 136.

    Martin JJ, Ceuterick C. Prenatal pathology in mucopolysaccharidoses: a comparison with postnatal cases. Clin Neuropathol. 1983;2:122–7.

  137. 137.

    Kubaski F, Brusius‐Facchin AC, Mason RW, Patel P, Burin MG, Michelin‐Tirelli K, et al. Elevation of glycosaminoglycans in the amniotic fluid of a fetus with mucopolysaccharidosis VII. Prenat Diagn. 2017;37:435–9.

  138. 138.

    Tomatsu S, Orii KO, Vogler C, Nakayama J, Levy B, Grubb JH, et al. Mouse model of N-acetylgalactosamine-6-sulfate sulfatase deficiency (Galns−/−) produced by targeted disruption of the gene defective in Morquio A disease. Hum Mol Genet. 2003;12:3349–58.

  139. 139.

    Vogler C, Birkenmeier EH, Sly WS, Levy B, Pegors C, Kyle JW, et al. A murine model of mucopolysaccharidosis VII. Gross and microscopic findings in beta-glucuronidase-deficient mice. Am J Pathol. 1990;136:207.

  140. 140.

    Ohashi A, Montaño AM, Colón JE, Oguma T, Luisiri A, Tomatsu S. Sacral dimple: incidental findings from newborn evaluation (Case Presentation). Acta Paediatr. 2009;98:768–9.

  141. 141.

    Gelb M. Newborn screening for lysosomal storage diseases: methodologies, screen positive rates, normalization of datasets, second-tier tests, and post-analysis tools. Int J Neonatal Screen. 2018;4:23.

  142. 142.

    Finnigan N, Roberts J, Mercer J, Jones SA. Home infusion with Elosulfase alpha (VimizimR) in a UK Paediatric setting. Mol Genet Metab Rep. 2018;14:15–8.

  143. 143.

    Coppa GV, Buzzega D, Zampini L, Maccari F, Galeazzi T, Pederzoli F, et al. Effect of 6 years of enzyme replacement therapy on plasma and urine glycosaminoglycans in attenuated MPS I patients. Glycobiology. 2010;20:1259–73.

  144. 144.

    de Ru MH, van der Tol L, van Vlies N, Bigger BW, Hollak CE, IJlst L, et al. Plasma and urinary levels of dermatan sulfate and heparan sulfate derived disaccharides after long-term enzyme replacement therapy (ERT) in MPS I: correlation with the timing of ERT and with total urinary excretion of glycosaminoglycans. J Inherit Metab Dis. 2013;36:247–55.

  145. 145.

    van der Tol L, de Ru MH, van Vlies N, Wagemans AH, IJlst L, Wijburg FA. MPS I: monitoring plasma and urine levels of dermatan and heparan sulfate during enzyme replacement therapy. Mol Genet Metab. 2012;2:S62.

  146. 146.

    Kubaski F, Suzuki Y, Orii K, Giugliani R, Church HJ, Mason RW, et al. Glycosaminoglycan levels in dried blood spots of patients with mucopolysaccharidoses and mucolipidoses. Mol Genet Metab. 2017;120:247–54.

  147. 147.

    Khan S, Alméciga-Díaz CJ, Sawamoto K, Mackenzie WG, Theroux MC, Pizarro C, et al. Mucopolysaccharidosis IVA and glycosaminoglycans. Mol Genet Metab. 2017;120:78–95.

  148. 148.

    Tomatsu S, Montaño AM, Oguma T, Dung VC, Oikawa H, de Carvalho TG, et al. Dermatan sulfate and heparan sulfate as a biomarker for mucopolysaccharidosis I. J Inherit Metab Dis. 2010;33:141–50.

  149. 149.

    Hendriksz CJ, Muenzer J, Vanderver A, Davis JM, Burton BK, Mendelsohn NJ, et al. Levels of glycosaminoglycans in the cerebrospinal fluid of healthy young adults, surrogate-normal children, and Hunter syndrome patients with and without cognitive impairment. Mol Genet Metab Rep. 2015;5:103–6.

  150. 150.

    Munoz‐Rojas MV, Vieira T, Costa R, Fagondes S, John A, Jardim LB, et al. Intrathecal enzyme replacement therapy in a patient with mucopolysaccharidosis type I and symptomatic spinal cord compression. Am J Med Genet Part A. 2008;146:2538–44.

  151. 151.

    Rowland LP, Pedley TA, editors. Merritt’s neurology. Philadelphia: Lippincott Williams & Wilkins; 2005.

  152. 152.

    A study to test the possibility of cross reaction induced by the idursulfase drug to GSK2788723. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01602601. Accessed 26 Jul 2019.

  153. 153.

    Accessdata.fda.gov. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761052lbl.pdf (2019). Accessed 26 Jul 2019.

  154. 154.

    Schulz A, Ajayi T, Specchio N, de Los Reyes E, Gissen P, Ballon D, et al. Study of intraventricular cerliponase alfa for CLN2 disease. New Engl J Med. 2018;378:1898–907.

  155. 155.

    Burton BK, Whiteman DA. HOS Investigators. Incidence and timing of infusion-related reactions in patients with mucopolysaccharidosis type II (Hunter syndrome) on idursulfase therapy in the real-world setting: a perspective from the Hunter Outcome Survey (HOS). Mol Genet Metab. 2011;103:113–20.

  156. 156.

    Kim KH, Decker C, Burton BK. Successful management of difficult infusion-associated reactions in a young patient with mucopolysaccharidosis type VI receiving recombinant human arylsulfatase B (galsulfase [Naglazyme]). Pediatrics. 2008;121:e714–7.

  157. 157.

    Accessdata.fda.gov. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125460s000lbl.pdf (2019). Accessed 26 Jul 2019.

  158. 158.

    Accessdata.fda.gov. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/125058s0186lbl.pdf (2019). Accessed 26 Jul 2019.

  159. 159.

    Accessdata.fda.gov. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125151s0152lbl.pdf (2019). Accessed 26 Jul 2019.

  160. 160.

    Accessdata.fda.gov. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125117s111lbl.pdf (2019). Accessed 26 Jul 2019.

  161. 161.

    Accessdata.fda.gov. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761047Orig1s000lbl.pdf (2019). Accessed 26 Jul 2019.

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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.

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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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