MPS I: Hematopoietic Stem Cell Transplantation and Enzyme Replacement Therapy

Hematopoietic stem cell transplantation (HSCT) in children with mucopolysaccharidosis type I (MPS I) involves replacing their deficient macrophages with ones that produce normal amounts of enzyme. [Weisstein: 2004] [Souillet: 2003] [Gassas: 2003] The success rate of HSCT depends upon several factors, such as the age of the patient and degree of cardiopulmonary involvement at time of transplant. Successful HSCT increases survival, reduces cognitive decline, facial coarseness and hepatosplenomegaly, improves hearing, and maintains normal heart function; however, the skeletal and joint manifestations, carpel tunnel syndrome manifestations, and corneal clouding continue to progress unabated.
Neuropsychological responses to HSCT are related to the age and intellectual capacity of the child at the time of the engraftment. If HSCT is done before evidence of significant developmental delay (usually under 2 years), there is some success in decreasing the degree and rate of cognitive decline. Children showing significant cognitive impairment prior to undergoing HSCT do not appear to benefit developmentally. As with any HSCT, there is a risk of graft-versus-host disease and up to a 20% risk of mortality. The use of ERT before HSCT might improve the clinical signs and symptoms (e.g., severe cardiomyopathy), which results in less transplantation-related complications. [Cox-Brinkman: 2006]
Enzyme replacement therapy (ERT)involves intravenous administration of recombinant alpha-L-iduronidase enzyme (Aldurazyme) to assist in the breakdown of accumulated GAGs and prevent further buildup. [Muenzer: 2004] [Wraith: 2005] [Wraith: 2004] Significant reduction in liver size, decrease in joint restriction, improvement in breathing and sleep apnea, and increased distance walked in the 6-minute walk test were demonstrated in individuals with attenuated MPS I. The benefit of ERT in those with severe disease has not been assessed. Because the recombinant enzyme is not thought to cross the blood-brain barrier, the best option to reduce the risk of cognitive impairment in those with severe MPS I remains early initiation of HSCT. As with HSCT, ERT does not appear to have significant beneficial effects on bone disease or corneal clouding.
The current dosing regimen for Aldurazyme involves premedication with anti-inflammatory and antihistamine drugs and intravenous weekly infusion of 100 units (0.58 mg)/kg of Aldurazyme over 4 hours. Although antibodies were present in all study patients in the clinical trials, they are not neutralizing and no known clinical consequences have been reported. Volumetric CT scan of liver and spleen can be used as an objective measure of the efficacy of enzyme replacement therapy during the first few months of treatment. Urine GAG assessments have not yet provided quantitative approaches to modify dosing regimens.
Unlike the use of intrathecal elaprase enzyme replacement therapy for Hunter syndrome (MPS II), the use of intrathecal administration of recombinant alpha-L-iduronidase is not available.

Resources

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Studies

Children and Adolescents with MPS I (ClinicalTrials.gov)

MPS I Registry
An ongoing, observational database that tracks natural history and outcomes of patients with MPS I. The Registry was initiated worldwide in April 2003 as an international observational program sponsored by BioMarin/Genzyme LLC and administered by Genzyme Corporation. Registration is voluntary, free, and confidential.

Authors & Reviewers

Last update/revision: May 2019
Current Authors and Reviewers:
Author: David Viskochil, MD, Ph.D.
Authoring history
2011: revision: David Viskochil, MD, Ph.D.A
2009: first version: Pilar L. Magoulas, MS, CGCA
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Cox-Brinkman J, Boelens JJ, Wraith JE, O'meara A, Veys P, Wijburg FA, Wulffraat N, Wynn RF.
Haematopoietic cell transplantation (HCT) in combination with enzyme replacement therapy (ERT) in patients with Hurler syndrome.
Bone Marrow Transplant. 2006;38(1):17-21. PubMed abstract

Gassas A, Sung L, Doyle JJ, Clarke JT, Saunders EF.
Life-threatening pulmonary hemorrhages post bone marrow transplantation in Hurler syndrome. Report of three cases and review of the literature.
Bone Marrow Transplant. 2003;32(2):213-5. PubMed abstract

Muenzer J, Fisher A.
Advances in the treatment of mucopolysaccharidosis type I.
N Engl J Med. 2004;350(19):1932-4. PubMed abstract

Souillet G, Guffon N, Maire I, Pujol M, Taylor P, Sevin F, Bleyzac N, Mulier C, Durin A, Kebaili K, Galambrun C, Bertrand Y, Froissart R, Dorche C, Gebuhrer L, Garin C, Berard J, Guibaud P.
Outcome of 27 patients with Hurler's syndrome transplanted from either related or unrelated haematopoietic stem cell sources.
Bone Marrow Transplant. 2003;31(12):1105-17. PubMed abstract

Weisstein JS, Delgado E, Steinbach LS, Hart K, Packman S.
Musculoskeletal manifestations of Hurler syndrome: long-term follow-up after bone marrow transplantation.
J Pediatr Orthop. 2004;24(1):97-101. PubMed abstract

Wraith JE.
The first 5 years of clinical experience with laronidase enzyme replacement therapy for mucopolysaccharidosis I.
Expert Opin Pharmacother. 2005;6(3):489-506. PubMed abstract

Wraith JE, Clarke LA, Beck M, Kolodny EH, Pastores GM, Muenzer J, Rapoport DM, Berger KI, Swiedler SJ, Kakkis ED, Braakman T, Chadbourne E, Walton-Bowen K, Cox GF.
Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase).
J Pediatr. 2004;144(5):581-8. PubMed abstract