A follow-up study of MPS I patients treated with laronidase enzyme replacement therapy for 6 years

Sifuentes, Monica; Doroshow, Robin Winkler; Hoft, Richard H.; Mason, Gregory R.; Walot, Irwin; Diament, Michael J.; Okazaki, Susan; Huff, Kenneth R.; Cox, Gerald F.; Swiedler, Stuart J.; Kakkis, Emil

doi:10.1016/j.ymgme.2006.08.007

Cited by 204 publications

(201 citation statements)

References 7 publications

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“…Mental retardation, for example, is well recognized and predicted to progress since the therapeutic enzyme can not go through the blood brain barrier. Development of cardiovascular complications including cardiomyopathy and valvular abnormalities are also well known in patients with MPS-I who have been treated with ERT (Sifuentes et al 2007). …”

Section: Discussionmentioning

confidence: 99%

The Transforming Growth Factor-Beta Signaling Pathway Involvement in Cardiovascular Lesions in Mucopolysaccharidosis-I

Yano

Pavlova

2012

JIMD Reports

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Mucopolysaccharidoses (MPS) are a group of genetic disorders due to deficiency of lysosomal enzymes resulting in impaired glycosaminoglycan metabolism. All types of MPS can present with cardiovascular manifestation, although MPS-I, II, and VI seem to have more severe involvement than the other types. Enzyme replacement therapy (ERT) is available for MPS-I, II, and VI. Cardiovascular changes including hypertrophic cardiomyopathy, thickened valvular lesions, and coronary artery lesions often poorly respond to ERT and are well known as leading causes of death in patients with MPS-I. The mechanisms to cause these changes in MPS-I have not been well characterized. Immunohistopathological studies were conducted on the cardiac specimens from a patient with MPS-I who died due to sudden cardiac failure.

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Section: Discussionmentioning

confidence: 99%

The Transforming Growth Factor-Beta Signaling Pathway Involvement in Cardiovascular Lesions in Mucopolysaccharidosis-I

Yano

Pavlova

2012

JIMD Reports

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“…For example, aortic insufficiency developed de novo or worsened in 89% of patients at 12 years after performing hematopoietic stem cell transplantation at ~2 years [30] and in 60% of patients at 4-6 years after starting enzyme replacement therapy [31,32]. Although pathological data were not available, progressive fragmentation of the elastic fibers likely contributed to worsening aortic valve function.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of elastase proteins results in aortic dilatation in mucopolysaccharidosis I mice

Tittiger

Knutsen

et al. 2008

Molecular Genetics and Metabolism

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Mucopolysaccharidosis I (MPS I), known as Hurler syndrome in the severe form, is a lysosomal storage disease due to -L-iduronidase (IDUA) deficiency. It results in fragmentation of elastin fibers in the aorta and heart valves via mechanisms that are unclear, but may result from the accumulation of the glycosaminoglycans heparan and dermatan sulfate. Elastin fragmentation causes aortic dilatation and valvular insufficiency, which can result in cardiovascular disease. The pathophysiology of aortic disease was evaluated in MPS I mice. MPS I mice have normal elastic fiber structure and aortic compliance at early ages, which suggests that elastin assembly is normal. Elastin fragmentation and aortic dilatation are severe at 6 months, which is temporally associated with marked increases in mRNA and enzyme activity for two elastin-degrading proteins, matrix metalloproteinase-12 (MMP-12) and cathepsin S. Upregulation of these genes likely involves activation of STAT proteins, which may be induced by structural stress to smooth muscle cells from accumulation of glycosaminoglycans in lysosomes. Neonatal intravenous injection of a retroviral vector normalized MMP-12 and cathepsin S mRNA levels and prevented aortic disease. We conclude that aortic dilatation in MPS I mice is likely due to degradation of elastin by MMP-12 and/or cathepsin S. This aspect of disease might be ameliorated by inhibition of the signal transduction pathways that upregulate expression of elastase proteins, or by inhibition of elastase activity. This could result in a treatment for patients with MPS I, and might reduce aortic aneurism formation in other disorders.

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“…Rare lysosomal storage disorders, such as mucopolysaccharidosis I (MPS I, Hurler syndrome), MPS VI (Maroteaux-Lamy syndrome), Gaucher disease, and Fabry disease are currently treated by intravenous enzyme replacement therapy [10][11][12][13][14][15][16]. Enzyme replacement therapy has successfully treated some aspects of the physical disease in MPS patients and has been well tolerated.…”

Section: Introductionmentioning

confidence: 99%

Intrathecal enzyme replacement therapy: Successful treatment of brain disease via the cerebrospinal fluid

Dickson

McEntee

Vogler

et al. 2007

Molecular Genetics and Metabolism

161

138

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Treatment of brain disease with recombinant proteins is difficult due to the blood-brain barrier. As an alternative to direct injections into the brain, we studied whether application of high concentrations of therapeutic enzymes via intrathecal (IT) injections could successfully drive uptake across the ependyma to treat brain disease. We studied IT enzyme replacement therapy with recombinant human iduronidase (rhIDU) in canine mucopolysaccharidosis I (MPS I, Hurler syndrome), a lysosomal storage disorder with brain and meningeal involvement. Monthly or quarterly IT treatment regimens with rhIDU achieved supranormal iduronidase enzyme levels in the brain, spinal cord, and spinal meninges. All regimens normalized total brain glycosaminoglycan (GAG) storage and reduced spinal meningeal GAG storage by 58-70%. The improvement in GAG storage levels persisted three months after the final IT dose. The successful use of enzyme therapy via the CSF represents a potentially useful approach for lysosomal storage disorders.

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A follow-up study of MPS I patients treated with laronidase enzyme replacement therapy for 6 years

Cited by 204 publications

References 7 publications

The Transforming Growth Factor-Beta Signaling Pathway Involvement in Cardiovascular Lesions in Mucopolysaccharidosis-I

The Transforming Growth Factor-Beta Signaling Pathway Involvement in Cardiovascular Lesions in Mucopolysaccharidosis-I

Upregulation of elastase proteins results in aortic dilatation in mucopolysaccharidosis I mice

Intrathecal enzyme replacement therapy: Successful treatment of brain disease via the cerebrospinal fluid

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