Vestronidase Alfa: A Review in Mucopolysaccharidosis VII

McCafferty, Emma H.; Scott, Lesley J.

doi:10.1007/s40259-019-00344-7

Cited by 40 publications

(29 citation statements)

References 25 publications

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“…LSDs are a group of about 50 inborn errors of metabolism (IEM) characterized by the lysosomal accumulation of partially or non-degraded molecules. Therapies for LSDs treatment may include: (1) to promote the storage clearance by administering an exogenous functional enzyme, (i.e., ERT); (2) to prevent the lysosomal accumulation of substrates by inhibiting their synthesis (i.e., substrate reduction therapy); (3) to enhance the enzyme activity of a mutated protein (i.e., PC therapy); and (4) to perform a bone marrow or stem cell transplantation, especially in those diseases with central nervous system (CNS) involvement [30][31][32][33][34][35][36]. Molecular characterization of LSDs has shown that in most of the cases the disease is caused by missense mutations [37,38].…”

Section: Use Of Pharmacological Chaperones In Lsdsmentioning

confidence: 99%

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

Diaz

Castillo

Rodríguez-López

et al. 2019

IJMS

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The mucopolysaccharidoses (MPS) are a group of 11 lysosomal storage diseases (LSDs) produced by mutations in the enzymes involved in the lysosomal catabolism of glycosaminoglycans. Most of the mutations affecting these enzymes may lead to changes in processing, folding, glycosylation, pH stability, protein aggregation, and defective transport to the lysosomes. It this sense, it has been proposed that the use of small molecules, called pharmacological chaperones (PCs), can restore the folding, trafficking, and biological activity of mutated enzymes. PCs have the advantages of wide tissue distribution, potential oral administration, lower production cost, and fewer issues of immunogenicity than enzyme replacement therapy. In this paper, we will review the advances in the identification and characterization of PCs for the MPS. These molecules have been described for MPS II, IVA, and IVB, showing a mutation-dependent enhancement of the mutated enzymes. Although the results show the potential of this strategy, further studies should focus in the development of disease-specific cellular models that allow a proper screening and evaluation of PCs. In addition, in vivo evaluation, both pre-clinical and clinical, should be performed, before they can become a real therapeutic strategy for the treatment of MPS patients.

show abstract

Section: Use Of Pharmacological Chaperones In Lsdsmentioning

confidence: 99%

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

Diaz

Castillo

Rodríguez-López

et al. 2019

IJMS

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Section: Discussionmentioning

confidence: 99%

“…A pivotal phase-III trial on vestronidase alfa has shown a significant decrease in urinary CS-DS excretion after 24 weeks [5]. While a marked amelioration of organomegaly and fatigue was observed, only a relative improvement in the mobility and the respiratory functions was noted [5]. The recombinant enzyme is directly infused into the bloodstream allowing its delivery to peripheral organs except for the brain, because of its inability to cross the blood-brain barrier.…”

Section: Discussionmentioning

confidence: 99%

“…At present, two therapeutic options are available: enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT). For ERT, a recombinant form of human GUS (vestronidase alpha) has been recently developed and used successfully [5], giving rise to a reduction of urinary GAGs and an improvement of the organomegaly [6]. However, the intravenously injected rhGUS does not cross the blood-brain-barrier and provides no effect on neurological signs, while HSCT can bring the enzyme into the brain via its secretion from donor-derived microglial cells and prevent or slow the neurological deterioration [7].…”

Section: Introductionmentioning

confidence: 99%

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Long-Term Follow-up Posthematopoietic Stem Cell Transplantation in a Japanese Patient with Type-VII Mucopolysaccharidosis

et al. 2020

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The effectiveness of hematopoietic stem cell transplantation (HSCT) for type-VII mucopolysaccharidosis (MPS VII, Sly syndrome) remains controversial, although recent studies have shown that it has a clinical impact. In 1998, Yamada et al. reported the first patient with MPS VII, who underwent HSCT at 12 years of age. Here, we report the results of a 22-year follow-up of that patient post-HSCT, who harbored the p.Ala619Val mutation associated with an attenuated phenotype. The purpose of this study was to evaluate changes in physical symptoms, the activity of daily living (ADL), and the intellectual status in the 34-year-old female MPS VII patient post-HSCT, and to prove the long-term effects of HSCT in MPS VII. Twenty-two years after HSCT, the β-glucuronidase activity in leukocytes remained at normal levels, and urinary glycosaminoglycan excretion was reduced and kept within normal levels. At present, she is capable of sustaining simple conversation, and her intellectual level is equivalent to that of a 6-year-old. She can walk alone and climb upstairs by holding onto a handrail, although she feels mild pain in the hip joint. The cervical vertebrae are fused with the occipital bone, causing dizziness and light-headedness when the neck is bent back. Overall, her clinical condition has been stabilized and kept well for long-term post-HSCT, indicating that HSCT is a therapeutic option for MPS VII.

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“…substrate reduction therapy), 3) to enhance the enzyme activity of a mutated protein (i.e. PC therapy), and 4) to perform a bone marrow or stem cell transplantation, especially in those diseases with central nervous system (CNS) involvement [30][31][32][33][34][35][36]. Molecular characterization of LSDs has shown that in most of the cases the disease is caused by missense mutations [37,38].…”

Section: Use Of Pharmacological Chaperones In Lsdsmentioning

confidence: 99%

Pharmacological Chaperones for the Mucopolysaccharidoses

Jc¹,

J²,

Rodríguez-López³

et al. 2019

Preprint

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The mucopolysaccharidoses (MPS) are a group of 11 lysosomal storage diseases (LSDs) produced by mutations in the enzymes involved in the lysosomal catabolism of glycosaminoglycans. Most of the mutations affecting these enzymes may lead to changes in processing, folding, glycosylation, pH stability, protein aggregation, and defective transport to the lysosomes. The use of small molecules, called pharmacological chaperones (PCs), that can restore the folding, trafficking and biological activity of mutated enzymes has been extensively explored in LSDs as a therapeutic alternative. PCs have the advantage of wide tissue distribution, potential oral administration, lower production cost, and fewer issues of immunogenicity. In this paper, we will review the advances in the identification and characterization of PCs for the MPS. These molecules, mainly based in molecules mimicking the enzyme substrates, have been described for MPS II, IVA, and IVB, showing a mutation-dependent enhancement of the mutated enzymes. Although the results show the potential of this strategy, further studies should focus in the development of disease-specific cellular models that allow a proper screening and evaluation of the identified PCs. In addition, in vivo evaluation, both pre-clinical and clinical, should be performed, before they can become a real therapeutic strategy for the treatment of MPS patients.

show abstract

Vestronidase Alfa: A Review in Mucopolysaccharidosis VII

Cited by 40 publications

References 25 publications

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

Long-Term Follow-up Posthematopoietic Stem Cell Transplantation in a Japanese Patient with Type-VII Mucopolysaccharidosis

Pharmacological Chaperones for the Mucopolysaccharidoses

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