Development of idursulfase therapy for mucopolysaccharidosis type II (Hunter syndrome): the past, the present and the future

Mucopolysaccharidosis type II (MPS II; Hunter syndrome; OMIM 309900) is a rare, multisystemic, progressive lysosomal storage disease caused by deficient activity of the iduronate-2-sulfatase (I2S) enzyme. Accumulation of the glycosaminoglycans dermatan sulfate and heparan sulfate results in a broad range of disease manifestations that are highly variable in presentation and severity; notably, approximately two-thirds of individuals are affected by progressive central nervous system involvement. Historically, management of this disease was palliative; however, during the 1990s, I2S was purified to homogeneity for the first time, leading to cloning of the corresponding gene and offering a means of addressing the underlying cause of MPS II using enzyme replacement therapy (ERT). Recombinant I2S (idursulfase) was produced for ERT using a human cell line and was shown to be indistinguishable from endogenous I2S. Preclinical studies utilizing the intravenous route of administration provided valuable insights that informed the design of the subsequent clinical studies. The pivotal Phase II/III clinical trial of intravenous idursulfase (Elaprase®; Shire, Lexington, MA, USA) demonstrated improvements in a range of clinical parameters; based on these findings, intravenous idursulfase was approved for use in patients with MPS II in the USA in 2006 and in Europe and Japan in 2007. Evidence gained from post-approval programs has helped to improve our knowledge and understanding of management of patients with the disease; as a result, idursulfase is now available to young pediatric patients, and in some countries patients have the option to receive their infusions at home. Although ERT with idursulfase has been shown to improve somatic signs and symptoms of MPS II, the drug does not cross the blood–brain barrier and so treatment of neurological aspects of the disease remains challenging. A number of novel approaches are being investigated, and these may help to improve the care of patients with MPS II in the future.

[1]  O. Gabrielli,et al.  Bone marrow transplantation in Hunter syndrome (mucopolysaccharidosis type II): two-year follow-up of the first Italian patient and review of the literature. , 1995, La Pediatria Medica e Chirurgica.

[2]  Y. Eto,et al.  Japan Elaprase Treatment (JET) study: idursulfase enzyme replacement therapy in adult patients with attenuated Hunter syndrome (Mucopolysaccharidosis II, MPS II). , 2010, Molecular genetics and metabolism.

[3]  Suraiya Rasheed,et al.  Characterization of a newly derived human sarcoma cell line (HT‐1080) , 1974, Cancer.

[4]  R. Giugliani,et al.  The natural history of growth in patients with Hunter syndrome: Data from the Hunter Outcome Survey (HOS). , 2013, Molecular genetics and metabolism.

[5]  R. Giugliani,et al.  Birth weight in patients with mucopolysaccharidosis type II: Data from the Hunter Outcome Survey (HOS) , 2017, Molecular genetics and metabolism reports.

[6]  William,et al.  The Metabolic and Molecular Bases of Inherited Disease (Scriver, C. R., Beaudet, A. L., Sly, W. S., Valle, D., Childs, B., Kinzler, K. W., and Vogelstein, B., eds., 8th ed., McGraw-Hill, New-York, 2001, 7012 p., $550.00) , 2004, Biochemistry (Moscow).

[7]  T. Mccauley,et al.  Pharmacokinetics and Bioavailability of a Therapeutic Enzyme (Idursulfase) in Cynomolgus Monkeys after Intrathecal and Intravenous Administration , 2015, PloS one.

[8]  R. Tomanin,et al.  Genistein reduces glycosaminoglycan levels in a mouse model of mucopolysaccharidosis type II , 2010, British journal of pharmacology.

[9]  J. Rutledge,et al.  Bone marrow transplantation in Hunter syndrome. , 1996, The Journal of pediatrics.

[10]  J. Quinn,et al.  Long-term follow-up of a patient transplanted for Hunter's disease type IIB: a case report and literature review. , 1994, Bone marrow transplantation.

[11]  G. Węgrzyn,et al.  Effect of rapid cessation of enzyme replacement therapy: a report of 5 cases and a review of the literature. , 2012, Molecular genetics and metabolism.

[12]  D. Hepner,et al.  Second symposium on the definition and management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. , 2006, The Journal of allergy and clinical immunology.

[13]  D. Brooks,et al.  Significance of immune response to enzyme-replacement therapy for patients with a lysosomal storage disorder. , 2003, Trends in molecular medicine.

[14]  Joseph Muenzer,et al.  Early initiation of enzyme replacement therapy for the mucopolysaccharidoses. , 2014, Molecular genetics and metabolism.

[15]  B. Burton,et al.  Importance of surgical history in diagnosing mucopolysaccharidosis type II (Hunter syndrome): Data from the Hunter Outcome Survey , 2010, Genetics in Medicine.

[16]  C. Eng,et al.  Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome , 2011, Genetics in Medicine.

[17]  B. Burton,et al.  The role of enzyme replacement therapy in severe Hunter syndrome—an expert panel consensus , 2011, European Journal of Pediatrics.

[18]  O. Bodamer,et al.  Mucopolysaccharidosis type II in females: case report and review of literature. , 2005, Pediatric neurology.

[19]  Y. Bertrand,et al.  Bone marrow transplantation in children with Hunter syndrome: outcome after 7 to 17 years. , 2009, The Journal of pediatrics.

[20]  J. Baenziger,et al.  A Major Step on the Road to Understanding a Unique Posttranslational Modification and Its Role in a Genetic Disease , 2003, Cell.

[21]  S. McCandless,et al.  A phase I/II clinical trial of enzyme replacement therapy in mucopolysaccharidosis II (Hunter syndrome). , 2007, Molecular genetics and metabolism.

[22]  F. Krummenauer,et al.  Cumulative incidence rates of the mucopolysaccharidoses in Germany , 2005, Journal of Inherited Metabolic Disease.

[23]  A. T. van der Ploeg,et al.  Hematopoietic cell transplantation for mucopolysaccharidosis patients is safe and effective: results after implementation of international guidelines. , 2015, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[24]  B. Burton,et al.  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). , 2011, Molecular genetics and metabolism.

[25]  K. Ahn,et al.  IgE‐mediated anaphylaxis and allergic reactions to idursulfase in patients with Hunter syndrome , 2013, Allergy.

[26]  C. Eng,et al.  Multidisciplinary Management of Hunter Syndrome , 2009, Pediatrics.

[27]  D. Whiteman,et al.  The relationship between anti-idursulfase antibody status and safety and efficacy outcomes in attenuated mucopolysaccharidosis II patients aged 5 years and older treated with intravenous idursulfase. , 2013, Molecular genetics and metabolism.

[28]  M. Prata,et al.  Functional analysis of splicing mutations in the IDS gene and the use of antisense oligonucleotides to exploit an alternative therapy for MPS II. , 2015, Biochimica et biophysica acta.

[29]  G. Węgrzyn,et al.  Improvement in the range of joint motion in seven patients with mucopolysaccharidosis type II during experimental gene expression‐targeted isoflavone therapy (GET IT) , 2011, American journal of medical genetics. Part A.

[30]  Qing-hui Zhou,et al.  Expression in CHO cells and pharmacokinetics and brain uptake in the Rhesus monkey of an IgG‐iduronate‐2‐sulfatase fusion protein , 2011, Biotechnology and bioengineering.

[31]  M. Beck,et al.  Prevalence and characterization of cardiac involvement in Hunter syndrome. , 2011, The Journal of pediatrics.

[32]  C. Kim,et al.  Mucopolysaccharidosis I, II, and VI: Brief review and guidelines for treatment , 2010, Genetics and molecular biology.

[33]  J. Gu,et al.  Bisecting GlcNAc Residues on Laminin-332 Down-regulate Galectin-3-dependent Keratinocyte Motility* , 2009, The Journal of Biological Chemistry.

[34]  W. Pardridge,et al.  Insulin receptor antibody‐iduronate 2‐sulfatase fusion protein: Pharmacokinetics, anti‐drug antibody, and safety pharmacology in Rhesus monkeys , 2014, Biotechnology and bioengineering.

[35]  C. Hunter.  A Rare Disease in Two Brothers , 1917, Proceedings of the Royal Society of Medicine.

[36]  M. Epstein,et al.  Guidelines for good pharmacoepidemiology practices (GPP) , 2008 .

[37]  B. Burton,et al.  Ten years of the Hunter Outcome Survey (HOS): insights, achievements, and lessons learned from a global patient registry , 2017, Orphanet Journal of Rare Diseases.

[38]  S. Sestito,et al.  Profile of idursulfase for the treatment of Hunter syndrome , 2015 .

[39]  A. Fischer,et al.  Outcomes of hematopoietic stem cell transplantation for Hurler's syndrome in Europe: a risk factor analysis for graft failure , 2007, Bone Marrow Transplantation.

[40]  A. Tylki-Szymańska,et al.  Growth pattern and growth prediction of body height in children with mucopolysaccharidosis type II , 2011, Acta paediatrica.

[41]  S. Braun,et al.  Metabolic correction and cross-correction of mucopolysaccharidosis type II (Hunter syndrome) by retroviral-mediated gene transfer and expression of human iduronate-2-sulfatase. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[42]  A. Hille-Rehfeld.  Mannose 6-phosphate receptors in sorting and transport of lysosomal enzymes. , 1995, Biochimica et biophysica acta.

[43]  R. Giugliani,et al.  Orthopedic manifestations in patients with mucopolysaccharidosis type II (Hunter syndrome) enrolled in the Hunter Outcome Survey , 2010, Orthopedic reviews.

[44]  L. de Meirleir,et al.  Mucopolysaccharidosis type II: European recommendations for the diagnosis and multidisciplinary management of a rare disease , 2011, Orphanet journal of rare diseases.

[45]  J. Hopwood,et al.  Human liver iduronate-2-sulphatase. Purification, characterization and catalytic properties. , 1989, The Biochemical journal.

[46]  Ana Martins,et al.  Guidelines for diagnosis and treatment of Hunter Syndrome for clinicians in Latin America , 2014, Genetics and molecular biology.

[47]  C. Eng,et al.  A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome) , 2006, Genetics in Medicine.

[48]  Y. Sohn,et al.  Phase I/II clinical trial of enzyme replacement therapy with idursulfase beta in patients with mucopolysaccharidosis II (Hunter Syndrome) , 2013, Orphanet Journal of Rare Diseases.

[49]  Kw Chan,et al.  Unrelated umbilical cord blood transplantation in infancy for mucopolysaccharidosis type IIB (Hunter syndrome) complicated by autoimmune hemolytic anemia , 2000, Bone Marrow Transplantation.

[50]  R. Giugliani,et al.  Initial report from the Hunter Outcome Survey , 2008, Genetics in Medicine.

[51]  W. Hwu,et al.  A multicenter, open-label study evaluating safety and clinical outcomes in children (1.4–7.5 years) with Hunter syndrome receiving idursulfase enzyme replacement therapy , 2013, Genetics in Medicine.

[52]  C. P. Morris,et al.  Hunter syndrome: isolation of an iduronate-2-sulfatase cDNA clone and analysis of patient DNA. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[53]  R. Tomanin,et al.  Gene therapy of Hunter syndrome: evaluation of the efficiency of muscle electro gene transfer for the production and release of recombinant iduronate-2-sulfatase (IDS). , 2008, Biochimica et biophysica acta.

[54]  J. L. Abrahams,et al.  Erythropoietin produced in a human cell line (Dynepo) has significant differences in glycosylation compared with erythropoietins produced in CHO cell lines. , 2011, Molecular pharmaceutics.

[55]  B. Burton,et al.  Home treatment with intravenous enzyme replacement therapy with idursulfase for mucopolysaccharidosis type II - data from the Hunter Outcome Survey. , 2010, Molecular genetics and metabolism.

[56]  R. Giugliani,et al.  Expression of the disease on female carriers of X-linked lysosomal disorders: a brief review , 2010, Orphanet journal of rare diseases.

[57]  L. de Meirleir,et al.  Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy , 2007, European Journal of Pediatrics.

[58]  B. Burton,et al.  Home infusion therapy is safe and enhances compliance in patients with mucopolysaccharidoses. , 2009, Molecular genetics and metabolism.

[59]  W. Jefferies,et al.  A Unique Carrier for Delivery of Therapeutic Compounds beyond the Blood-Brain Barrier , 2008, PloS one.

[60]  A. Mehta,et al.  Home therapy for lysosomal storage disorders. , 2007, British journal of nursing.

[61]  R. Giugliani,et al.  Idursulfase treatment of Hunter syndrome in children younger than 6 years: Results from the Hunter Outcome Survey , 2011, Genetics in Medicine.

[62]  R. Giugliani,et al.  The mucopolysaccharidoses. , 1976, Journal of medical genetics.

[63]  Kurt Brorson,et al.  Removal of endogenous retrovirus‐like particles from CHO‐cell derived products using Q sepharose fast flow chromatography , 2009, Biotechnology progress.

[64]  C. Hendriksz,et al.  Mortality and cause of death in mucopolysaccharidosis type II—a historical review based on data from the Hunter Outcome Survey (HOS) , 2009, Journal of Inherited Metabolic Disease.

[65]  M. Heartlein,et al.  Safety Evaluation of Chronic Intrathecal Administration of Idursulfase-IT in Cynomolgus Monkeys , 2011, Toxicologic pathology.

[66]  C. Marshall,et al.  Activated N-ras controls the transformed phenotype of HT1080 human fibrosarcoma cells , 1987, Cell.

[67]  P. Lockman,et al.  Anti-cancer Antibody Trastuzumab-Melanotransferrin Conjugate (BT2111) for the Treatment of Metastatic HER2+ Breast Cancer Tumors in the Brain: an In-Vivo Study , 2016, Pharmaceutical Research.

[68]  J. Dambrosia,et al.  Replacement therapy for inherited enzyme deficiency--macrophage-targeted glucocerebrosidase for Gaucher's disease. , 1991, The New England journal of medicine.

[69]  B. Burton,et al.  Diagnosing Hunter syndrome in pediatric practice: practical considerations and common pitfalls , 2012, European Journal of Pediatrics.

[70]  M. Beck.  Mucopolysaccharidosis Type II (Hunter Syndrome): clinical picture and treatment. , 2011, Current pharmaceutical biotechnology.

[71]  D. Hughes,et al.  Intravenous enzyme replacement therapy: better in home or hospital? , 2006, British journal of nursing.

[72]  Laurie D. Smith,et al.  Enzyme Replacement Therapy in Mucopolysaccharidosis II Patients Under 1 Year of Age. , 2014, JIMD reports.

[73]  A. Keilmann,et al.  Hearing loss in patients with mucopolysaccharidosis II: Data from HOS – the Hunter Outcome Survey , 2012, Journal of Inherited Metabolic Disease.

[74]  D. Wheatley.  Pericentriolar virus-like particles in Chinese hamster ovary cells. , 1974, The Journal of general virology.

[75]  I. Young,et al.  THE NATURAL HISTORY OF THE SEVERE FORM OF HUNTER'S SYNDROME: A STUDY BASED ON 52 CASES , 1983, Developmental medicine and child neurology.

[76]  E. Young,et al.  Long-term follow-up following bone marrow transplantation for Hunter disease , 1999, Journal of Inherited Metabolic Disease.

[77]  J. E. Wraith,et al.  Home treatment with Elaprase® and Naglazyme® is safe in patients with mucopolysaccharidoses types II and VI, respectively , 2008, Journal of Inherited Metabolic Disease.

[78]  Z. Żuber,et al.  Enzyme replacement therapy for mucopolysaccharidosis II from 3 months of age: a 3‐year follow‐up , 2012, Acta paediatrica.

[79]  C. W. Hall,et al.  Hurler and Hunter Syndromes: Mutual Correction of the Defect in Cultured Fibroblasts , 1968, Science.

[80]  Gary Walsh,et al.  Post-translational modifications in the context of therapeutic proteins , 2006, Nature Biotechnology.

[81]  Richard E Gliklich,et al.  GRACE principles: recognizing high-quality observational studies of comparative effectiveness. , 2010, The American journal of managed care.

[82]  R. A. Wevers,et al.  The frequency of lysosomal storage diseases in The Netherlands , 1999, Human Genetics.

[83]  E. Miebach.  Management of infusion-related reactions to enzyme replacement therapy in a cohort of patients with mucopolysaccharidosis disorders. , 2009, International journal of clinical pharmacology and therapeutics.

[84]  R. Schiffmann,et al.  Enzyme Therapy in Type 1 Gaucher Disease: Comparative Efficacy of Mannose-Terminated Glucocerebrosidase from Natural and Recombinant Sources , 1995, Annals of Internal Medicine.

[85]  A. Lai,et al.  Pentosan Polysulfate: A Novel Therapy for the Mucopolysaccharidoses , 2013, PloS one.

[86]  P. Harper,et al.  Mild form of Hunter's syndrome: clinical delineation based on 31 cases. , 1982, Archives of disease in childhood.

[87]  R. Brady.  The sphingolipidoses. , 1966, The New England journal of medicine.

[88]  Ich Harmonised,et al.  INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED GUIDELINE GENERAL CONSIDERATIONS FOR CLINICAL STUDIES E8(R1) , 2019 .

[89]  M. Mascelli,et al.  A phase I/II study of intrathecal idursulfase-IT in children with severe mucopolysaccharidosis II , 2015, Genetics in Medicine.

[90]  G. Węgrzyn,et al.  Cell cycle is disturbed in mucopolysaccharidosis type II fibroblasts, and can be improved by genistein. , 2016, Gene.

[91]  D. Whiteman,et al.  Immunogenicity of idursulfase and clinical outcomes in very young patients (16 months to 7.5 years) with mucopolysaccharidosis II (Hunter syndrome) , 2015, Orphanet Journal of Rare Diseases.

[92]  A. Ballabio,et al.  Correction of Hunter syndrome in the MPSII mouse model by AAV2/8-mediated gene delivery. , 2006, Human molecular genetics.

[93]  R. Giugliani,et al.  A clinical study of 77 patients with mucopolysaccharidosis type II , 2007, Acta paediatrica.

[94]  C. Eng,et al.  Recognition and Diagnosis of Mucopolysaccharidosis II (Hunter Syndrome) , 2008, Pediatrics.

[95]  Peter A Merkel,et al.  Clinical research for rare disease: opportunities, challenges, and solutions. , 2009, Molecular genetics and metabolism.

[96]  Masao Kobayashi,et al.  Effects of idursulfase enzyme replacement therapy for Mucopolysaccharidosis type II when started in early infancy: comparison in two siblings. , 2013, Molecular genetics and metabolism.

[97]  W. Krivit,et al.  Hematopoietic cell transplantation for mucopolysaccharidosis IIB (Hunter syndrome). , 2000, Bone marrow transplantation.

[98]  J. DaCosta,et al.  Preclinical dose ranging studies for enzyme replacement therapy with idursulfase in a knock-out mouse model of MPS II. , 2007, Molecular genetics and metabolism.

[99]  P. Meikle,et al.  Prevalence of lysosomal storage disorders. , 1999, JAMA.

[100]  G. Pintos-Morell,et al.  First experience of enzyme replacement therapy with idursulfase in Spanish patients with Hunter syndrome under 5 years of age: case observations from the Hunter Outcome Survey (HOS). , 2010, European journal of medical genetics.

[101]  M. Scarpa.  Evaluation of idursulfase for the treatment of mucopolysaccharidosis II (Hunter syndrome) , 2013 .

[102]  A. Varki,et al.  Implications of the presence of N-glycolylneuraminic acid in recombinant therapeutic glycoproteins , 2010, Nature Biotechnology.

[103]  C. Deduve.  FROM CYTASES TO LYSOSOMES. , 1964, Federation proceedings.

[104]  J. Thompson,et al.  Biochemical and molecular analysis in a patient with the severe form of Hunter syndrome after bone marrow transplantation. , 1996, American journal of medical genetics.

[105]  R. Tomanin,et al.  Non‐viral transfer approaches for the gene therapy of mucopolysaccharidosis type II (Hunter syndrome) , 2002, Acta paediatrica (Oslo, Norway : 1992). Supplement.

[106]  C. Giussani,et al.  Enzymatic replacement therapy for Hunter disease: Up to 9 years experience with 17 patients , 2015, Molecular genetics and metabolism reports.

[107]  O. Gabrielli,et al.  Bone marrow transplantation in Hunter syndrome , 1995, Journal of Inherited Metabolic Disease.

[108]  R. Giugliani,et al.  The effect of idursulfase on growth in patients with Hunter syndrome: data from the Hunter Outcome Survey (HOS). , 2013, Molecular genetics and metabolism.