View source for Iduronidase

{{Short description|Mammalian protein found in ''Homo sapiens''}}
{{Use dmy dates|date=August 2024}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{infobox protein
| Name = iduronidase, α-L-
| caption = 
| image = 
| width = 
| HGNCid = 5391
| Symbol = IDUA
| AltSymbols = 
| EntrezGene = 3425
| OMIM = 252800
| RefSeq = NM_000203
| UniProt = P35475
| PDB = 
| ECnumber = 3.2.1.76
| Chromosome = 4
| Arm = p
| Band = 16.3
| LocusSupplementaryData =
}}

'''Iduronidase''' ({{EnzExplorer|3.2.1.76}}, ''<small>L</small>-iduronidase'', ''α-<small>L</small>-iduronidase'', ''laronidase''), sold as '''Aldurazyme''', is an enzyme with the [[List of enzymes|systematic name]] ''glycosaminoglycan α-<small>L</small>-iduronohydrolase''.<ref>{{cite journal | vauthors = Matalon R, Cifonelli JA, Dorfman A | title = L-Iduronidase in cultured human fibroblasts and liver | journal = Biochemical and Biophysical Research Communications | volume = 42 | issue = 2 | pages = 340–5 | date = January 1971 | pmid = 4993544 | doi = 10.1016/0006-291x(71)90108-2 }}</ref><ref>{{cite journal | vauthors = Rome LH, Garvin AJ, Neufeld EF | title = Human kidney α-L-iduronidase: purification and characterization | journal = Archives of Biochemistry and Biophysics | volume = 189 | issue = 2 | pages = 344–53 | date = August 1978 | pmid = 30407 | doi = 10.1016/0003-9861(78)90221-7 }}</ref><ref>{{cite journal | title = Preparation of (aryl α-L-idopyranosid)uronic acids | vauthors = Srivastava RM, Hudson N, Seymour FR, Weissman B | journal = Carbohydr. Res. |year = 1978 |volume = 60 | issue = 2 |pages = 315–326 |doi=10.1016/s0008-6215(78)80038-x}}</ref> It [[catalysis|catalyses]] the [[hydrolysis]] of unsulfated α-<small>L</small>-iduronosidic linkages in [[dermatan sulfate]].<ref name="Aldurazyme">[https://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/ucm083688.pdf Aldurazyme (Laronidase)]. BioMarin Pharmaceuticals Inc.  FDA website. Retrieved 6 December 2015.</ref>

It is a glycoprotein enzyme found in the [[lysosome]]s of cells. It is involved in the degeneration of [[glycosaminoglycan]]s such as [[dermatan sulfate]] and [[heparan sulfate]]. The enzyme acts by hydrolyzing the terminal α-<small>L</small>-iduronic acid residues of these molecules, degrading them. The protein is reported as having a mass of approximately 83 kDa.<ref name="Aldurazyme"/>

== Pathology ==
A deficiency in the IDUA protein is associated with [[mucopolysaccharidoses]] (MPS). MPS, a type of lysosomal storage disease, is typed I through VII. Type I is known as [[Hurler syndrome]] and type I,S is known as [[Scheie syndrome]], which has a milder prognosis compared to Hurler's. In this syndrome, [[glycosaminoglycans]] accumulate in the [[lysosome]]s and cause substantial disease in many different tissues of the body. IDUA mutations result in the MPS 1 [[phenotype]], which is inherited in an [[autosomal recessive]] fashion.<ref>{{cite journal | vauthors = Scott HS, Nelson PV, Litjens T, Hopwood JJ, Morris CP | title = Multiple polymorphisms within the alpha-L-iduronidase gene (IDUA): implications for a role in modification of MPS-I disease phenotype | journal = Human Molecular Genetics | volume = 2 | issue = 9 | pages = 1471–3 | date = September 1993 | pmid = 8242073 | doi = 10.1093/hmg/2.9.1471 }}</ref>
The defective α-<small>L</small>-iduronidase results in an accumulation of heparan and dermatan sulfate within phagocytes, endothelium, smooth muscle cells, neurons, and fibroblasts. Under electron microscopy these structures present as laminated structures called Zebra bodies.

Prenatal diagnosis of this enzyme deficiency is possible.

== Aldurazyme ==

=== General ===
Aldurazyme is the name of the commercialized variant of the enzyme iduronidase, which hydrolyzes the α-<small>L</small>-iduronic acid residues of [[dermatan sulfate]] and [[heparin sulfate]].  Produced in Chinese hamster ovaries by recombinant DNA technology, Aldurazyme is manufactured by BioMarin Pharmaceutical Inc. and distributed by Genzyme Corporation (a subsidiary of Sanofi). Aldurazyme is administered as a slow intravenous infusion. The recombinant enzyme is 628 amino acids in length with 6 ''N''-linked oligosaccharide modification sites and two oligosaccharide chains terminating in mannose sugars.<ref name="Aldurazyme"/>

=== Medical uses ===
{{Infobox drug
| image             = 
| width             = 
| alt               = 
| caption           = 
| USAN              = Laronidase
| JAN               = Laronidase (genetical recombination)

<!-- Clinical data -->
| pronounce         = 
| tradename         = Aldurazyme
| Drugs.com         = {{Drugs.com|monograph|laronidase}}
| MedlinePlus       = 
| DailyMedID        = Laronidase
| pregnancy_AU      = B2
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Laronidase (Aldurazyme) Use During Pregnancy | website=Drugs.com | date=11 December 2019 | url=https://www.drugs.com/pregnancy/laronidase.html | access-date=14 April 2020}}</ref>
| pregnancy_category= 
| routes_of_administration = [[Intravenous]]
| class             = 
| ATC_prefix        = A16
| ATC_suffix        = AB05
| ATC_supplemental  =

<!-- Legal status -->
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_AU_comment = 
| legal_BR =  <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
| legal_BR_comment = 
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment = 
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment = 
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment = 
| legal_UK = POM
| legal_UK_comment = <ref>{{cite web | title=Aldurazyme 100 U/ml concentrate for solution for infusion - Summary of Product Characteristics (SmPC) | website=(emc) | date=2 January 2019 | url=https://www.medicines.org.uk/emc/product/216/smpc | access-date=14 April 2020}}</ref>
| legal_US = Rx-only
| legal_US_comment = 
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Aldurazyme EPAR" />
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment = 
| legal_status      = Rx-only

<!-- Pharmacokinetic data -->
| bioavailability   = 
| protein_bound     = 
| metabolism        = 
| metabolites       = 
| onset             = 
| elimination_half-life = 
| duration_of_action = 
| excretion         =

<!-- Identifiers -->
| CAS_number        = 210589-09-6
| CAS_supplemental  = 
| PubChem           = 
| IUPHAR_ligand     = 
| DrugBank          = DB00090
| ChemSpiderID      = 
| UNII              = WP58SVM6R4
| KEGG              = D04670
| ChEBI             = 
| ChEMBL            = 1201595
| NIAID_ChemDB      = 
| PDB_ligand        = 
| synonyms          = alpha-L-Idosiduronase

<!-- Chemical and physical data -->
| IUPAC_name        = 
| C = 3567 | H = 5645 | N = 921 | O = 1261 | S = 12 | P = 4
| SMILES            = 
| StdInChI          = 
| StdInChI_comment  = 
| StdInChIKey       = 
| density           = 
| density_notes     = 
| melting_point     = 
| melting_high      = 
| melting_notes     = 
| boiling_point     = 
| boiling_notes     = 
| solubility        = 
| sol_units         = 
| specific_rotation = 
}}

Aldurazyme is indicated in the US for people with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and for people with the Scheie form who have moderate to severe symptoms.<ref name="Aldurazyme FDA label">{{cite web | title=Aldurazyme- laronidase injection, solution, concentrate | website=DailyMed | date=12 December 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a80ac249-cae4-41f3-88bb-344088b20e60 | access-date=14 April 2020}}</ref>

Aldurazyme is indicated in the EU for long-term enzyme replacement therapy in patients with a confirmed diagnosis of mucopolysaccharidosis I (MPS I; α-<small>L</small>-iduronidase deficiency) to treat the nonneurological manifestations of the disease.<ref name="Aldurazyme EPAR">{{cite web | title=Aldurazyme EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/aldurazyme | access-date=14 April 2020}}</ref>

Aldurazyme was approved for medical use in the United States and in the European Union in 2003.<ref>{{cite web | title=Laronidase Product Approval Information - Licensing Action | website=U.S. [[Food and Drug Administration]] (FDA) | date=30 September 2016 | url= https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm080438.htm | archive-url=https://web.archive.org/web/20170118085125/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm080438.htm | archive-date = 18 January 2017 | url-status=dead | access-date=14 April 2020}}</ref><ref>{{cite web | title=Aldurazyme: FDA-Approved Drugs | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=125058 | access-date=14 April 2020}}</ref><ref name="Aldurazyme FDA label" /><ref name="Aldurazyme EPAR" />

=== Pre-clinical work ===
Dosing for human clinical studies was based on canine MPS I studies.<ref name= "Clinical">[https://www.aldurazyme.com/healthcare/about-aldurazyme/clinical-trials.aspx "Clinical Trials Summary."] {{Webarchive|url=https://web.archive.org/web/20180627005231/https://www.aldurazyme.com/healthcare/about-aldurazyme/clinical-trials.aspx |date=27 June 2018 }} Adurazyme (Laronidase) website. Accessed 7 December 2015.</ref>

=== Clinical trials ===
Three clinical trials were performed to establish the pharmacology, efficacy, and safety of weekly intravenous administration of the drug.  These studies included a Phase I open-label study, a Phase III randomized, double-blind, placebo-controlled study, and a Phase III open-label extension study.  A Phase II Young Pediatric study was also conducted.<ref name= "Clinical"/>

Clinical trials and post-market safety data indicate that the most common adverse side effect of Aldurazyme is allergic reaction.<ref name= "Clinical"/> In order to prevent allergic reaction and respiratory distress, the packet insert of Aldurazyme suggests that patients be administered antihistamines before infusion.<ref name= "Clinical"/> Allergic reaction occurs in approximately 1% of patients.  It is recommended that patients who are high-risk for respiratory distress be given their infusion in a facility equipped to deal with an anaphylactic response.<ref name= "Clinical"/> (High-risk factors include sleep apnea, respiratory impairment, respiratory illness, or previous experience with allergic reaction to Aldurazyme.  It is noted that risk-benefit must be weighed for patients with history of severe allergic response as to whether the drug should be administered again.)<ref name= "Clinical"/> In a 2002 memorandum, Melanie Hartsough, Ph.D., DTP of the FDA's Department of Health and Human Services stated, "Aggregation of product could enhance immune responses, specifically neutralizing antibody, which may limit the response to therapy, whereas highly deaggregated product may induce immune tolerance." It appears that she then went on to ask for further justification of some relevant aspect of the production process, though the majority of this particular memorandum has not been publicly released and it is unclear as to whether this concern is relevant to the high rate of allergic response to this drug.<ref>{{cite web | vauthors = Hartsough M | url = https://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/ucm083694.pdf | archive-url = https://web.archive.org/web/20101122150943/https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm083694.pdf | archive-date = 22 November 2010 | url-status = dead | title = Aldurazyme CMC Product Review | date = 28 August 2002 | publisher = United States Food and Drug Administration }}</ref>

Additionally, it is recommended that patients be administered antipyretics before use. According to Aldurazyme's website, the most common adverse effects observed in a 26-week, placebo-controlled clinical trial of patients 6 years old or older are  flushing, pyrexia, headache, and rash.  Flushing was noted in 23% of patients, or five people, in this relatively small clinical study. This trial was extended.  In the extension, it was noted that abdominal pain and infusion-site reaction occurred in some patients.<ref name= "Clinical"/>

The website also states that in a 52-week open-label uncontrolled clinical trial, the most common serious reactions in children younger than 6 were "otitis media (20%), and central venous catherization required for ALDURAZYME infusion (15%). The most commonly reported adverse reactions in patients 6 years and younger were infusion reactions reported in 35% (7 of 20) of patients and included pyrexia (30%), chills (20%), blood pressure increased (10%), tachycardia (10%), and oxygen saturation decreased (10%). Other commonly reported infusion reactions occurring in ≥5% of patients were pallor, tremor, respiratory distress, wheezing, crepitations (pulmonary), pruritus, and rash."<ref name= "Clinical"/>

A Phase IV clinical trial is currently{{when|date=April 2020}} recruiting participants to investigate whether Aldurazyme passes through breastmilk and whether it has any effect on nursing infants.<ref>{{cite web | title=A Study of the Effect of Aldurazyme (Laronidase) Treatment on Lactation in Female Patients With Mucopolysaccharidosis I (MPS I) and Their Breastfed Infants | website=ClinicalTrials.gov | date=5 January 2007 | url=https://clinicaltrials.gov/ct2/show/NCT00418821 | access-date=14 April 2020}}</ref> {{update inline|date=April 2020}}

=== Regulation ===
Aldurazyme was the first drug approved by the United States Food and Drug Administration to be marketed as a treatment for MPS I.  It was approved in April 2003.  Marketing authorization in the European Union was granted in June 2003 by the European Commission.  Aldurazyme enjoys [[orphan drug]] status in both the United States and the European Union, though in both its orphan drug exclusivity period has expired.  (Orphan drug exclusivity, which prevents the FDA or similar European body from approving the same drug proposed by another company for the same listed use lasts only seven years in the United States and ten years in the European Union.)  Aldurazyme was granted orphan designation for Treatment of patients with mucopolysaccharidosis-I on 24 September 1997.<ref name= "biomarin">[http://www.biomarin.com/products/aldurazyme/ Aldurazyme (laronidase) for MPS I] {{Webarchive|url=https://web.archive.org/web/20201001151932/https://www.biomarin.com/products/aldurazyme/ |date=1 October 2020 }}. Biomarin website. Accessed 6 December 2015.</ref><ref name="SEC 10-K Feb 2011">[http://www.wikinvest.com/stock/BioMarin_Pharmaceutical_%28BMRN%29/Filing/10-K/2011/F94401752 United States Securities and Exchange Commission Form 10-K] {{Webarchive|url=https://web.archive.org/web/20181008111728/http://www.wikinvest.com/stock/BioMarin_Pharmaceutical_%28BMRN%29/Filing/10-K/2011/F94401752 |date=8 October 2018 }}. BioMarin Pharmaceuticals. 24 February 2011.  Accessed 7 December 2015.</ref><ref>[http://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfm?Index_Number=106097 FDA Orphan Drug Designations and Approvals] {{Webarchive|url=https://web.archive.org/web/20210923044602/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfm?Index_Number=106097 |date=23 September 2021 }}. FDA website. Accessed 15 December 2015.</ref>

As of 2014, Aldurazyme was mandated to be produced using [[Good Manufacturing Practices]] (GMP) and, along with several other recombinant enzyme products produced by Biomarin, was manufactured at the production facility located in Novato, California.  Both packaging and vialing were performed by contractors. All suppliers and contractors also are mandated to follow GMP, and they, as well as BioMarin, are subject to inspection and review. BioMarin's facility has received both FDA and European Commission approval.<ref name= "D 2014">[http://www.wikinvest.com/stock/BioMarin_Pharmaceutical_(BMRN)/Filing/10-K/2015/F122541544 United States Securities and Exchange Commission Form 10-K] {{Webarchive|url=https://web.archive.org/web/20181008111736/http://www.wikinvest.com/stock/BioMarin_Pharmaceutical_(BMRN)/Filing/10-K/2015/F122541544 |date=8 October 2018 }}. BioMarin Pharmaceuticals. For the fiscal year ended 31 December 2014.  Accessed 6 December 2015.</ref>

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite book | vauthors = Clarke LA | chapter=Mucopolysaccharidosis Type I | title=GeneReviews | date=11 February 2016 | pmid=20301341 | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK1162/ | url= https://www.ncbi.nlm.nih.gov/books/NBK1116/ | location=Seattle (WA) | publisher=University of Washington | issn=2372-0697 | name-list-style = vanc }}
{{refend}}

== External links ==
* {{cite web | title=Mucopolysaccharidosis type I | website=MedlinePlus | url=https://medlineplus.gov/ency/article/001204.htm | id=NBK1162 }}
* {{MeshName|Iduronidase}}

{{Glycosaminoglycan catabolism}}
{{Sugar hydrolases}}
{{Enzymes}}
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[[Category:EC 3.2.1]]
[[Category:Orphan drugs]]
[[Category:Sanofi]]