Novel Enzyme Replacement Therapies for Neuropathic Mucopolysaccharidoses

Sato, Yoichiro; Okuyama, Torayuki

doi:10.3390/ijms21020400

Cited by 40 publications

(48 citation statements)

References 45 publications

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“…The conjugation of a therapeutic recombinant protein to a TH enables the transport of the protein drug across the BBB. The receptors mainly used for this purpose are insulin receptors (IR) and transferrin receptors (TfR), which transport circulating insulin and transferrin across the BBB, respectively, in addition to receptor-specific monoclonal antibodies [131,132]. The insulin receptor was exploited as a fusion protein with IDS in Rhesus monkeys, showing a safety profile for chronic treatment with weekly intravenous infusions of 3-30 mg/kg of drug [133].…”

Section: Improvements Of Ert Traditional Protocolmentioning

confidence: 99%

Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment

D’Avanzo

Rigon

Zanetti

et al. 2020

IJMS

107

145

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Mucopolysaccharidosis type II (MPS II, Hunter syndrome) was first described by Dr. Charles Hunter in 1917. Since then, about one hundred years have passed and Hunter syndrome, although at first neglected for a few decades and afterwards mistaken for a long time for the similar disorder Hurler syndrome, has been clearly distinguished as a specific disease since 1978, when the distinct genetic causes of the two disorders were finally identified. MPS II is a rare genetic disorder, recently described as presenting an incidence rate ranging from 0.38 to 1.09 per 100,000 live male births, and it is the only X-linked-inherited mucopolysaccharidosis. The complex disease is due to a deficit of the lysosomal hydrolase iduronate 2-sulphatase, which is a crucial enzyme in the stepwise degradation of heparan and dermatan sulphate. This contributes to a heavy clinical phenotype involving most organ-systems, including the brain, in at least two-thirds of cases. In this review, we will summarize the history of the disease during this century through clinical and laboratory evaluations that allowed its definition, its correct diagnosis, a partial comprehension of its pathogenesis, and the proposition of therapeutic protocols. We will also highlight the main open issues related to the possible inclusion of MPS II in newborn screenings, the comprehension of brain pathogenesis, and treatment of the neurological compartment.

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Section: Improvements Of Ert Traditional Protocolmentioning

confidence: 99%

Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment

D’Avanzo

Rigon

Zanetti

et al. 2020

IJMS

107

145

View full text Add to dashboard Cite

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“…5,6 Furthermore, progressive deterioration of the CNS is common in MPS-I, II, III, and VII, 7 although the details of the neurodegenerative progression in MPS have not been fully elucidated. 8 Intravenous enzyme replacement therapy (ERT) with recombinant human IDS (idursulfase, Elaprase) for MPS II is effective for most of the aforementioned peripheral symptoms [9][10][11] but not, because of the BBB, for the CNS disorders. As a result, progressive neurocognitive deterioration in MPS II remains a critical issue for patients and researchers alike.…”

Section: Introductionmentioning

confidence: 99%

A Phase 2/3 Trial of Pabinafusp Alfa, IDS Fused with Anti-Human Transferrin Receptor Antibody, Targeting Neurodegeneration in MPS-II

Eto²,

et al. 2021

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Pabinafusp alfa (JR-141) is a novel enzyme drug that crosses the blood-brain barrier by transcytosis via transferrin receptors. In order to establish its efficacy and safety, a multicenter, singlearm, open-label phase 2/3 clinical trial was conducted in 28 Japanese patients with mucopolysaccharidosis II (MPS-II, Hunter syndrome) by intravenous administrations of 2.0 mg/kg of pabinafusp alfa for 52 weeks. The primary efficacy endpoint was changes in heparan sulfate (HS) concentrations in the cerebrospinal fluid (CSF). Secondary endpoints included assessments of neurocognitive development for central efficacy, and changes in plasma HS and dermatan sulfate (DS) concentrations for peripheral efficacy. HS concentrations in the CSF significantly decreased from baseline to week 52 (p < 0.001), suggesting continuous inhibition of substrate accumulations in the CNS, i.e., hitherto unaddressed progressive neurodegeneration. Evaluations of neurocognitive developments showed positive changes in 21 of the 28 patients. Serum HS and DS concentrations, liver and spleen volumes, and other assessments suggested the peripheral efficacy of pabinafusp alfa was comparable to that of idursulfase. Drug-related adverse events were mild or moderate in severity, transient, and manageable. The results establish delivery across the BBB of pabinafusp alfa as an effective therapeutic for treating both the CNS and peripheral symptoms of patients with MPS-II.

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“…The decision on whether to continue the treatment or not is made together with the family on the basis of periodic clinical evaluations [26]. The paper by Sato and Okuyama, in this Special Issue, illustrates the available information on clinical trials with novel enzyme replacement therapies for neuropathic MPSs [27].…”

Section: Introductionmentioning

confidence: 99%

Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations

Parini

Deodato

2020

IJMS

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The aim of this review is to summarize the evidence on efficacy, effectiveness and safety of intravenous enzyme replacement therapy (ERT) available for mucopolysaccharidoses (MPSs) I, II, IVA, VI and VII, gained in phase III clinical trials and in observational post-approval studies. Post-marketing data are sometimes conflicting or controversial, possibly depending on disease severity, differently involved organs, age at starting treatment, and development of anti-drug antibodies (ADAs). There is general agreement that ERT is effective in reducing urinary glycosaminoglycans and liver and spleen volume, while heart and joints outcomes are variable in different studies. Effectiveness on cardiac valves, trachea and bronchi, hearing and eyes is definitely poor, probably due to limited penetration in the specific tissues. ERT does not cross the blood–brain barrier, with the consequence that the central nervous system is not cured by intravenously injected ERT. All patients develop ADAs but their role in ERT tolerance and effectiveness has not been well defined yet. Lack of reliable biomarkers contributes to the uncertainties about effectiveness. The data obtained from affected siblings strongly indicates the need of neonatal screening for treatable MPSs. Currently, other treatments are under evaluation and will surely help improve the prognosis of MPS patients.

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Novel Enzyme Replacement Therapies for Neuropathic Mucopolysaccharidoses

Cited by 40 publications

References 45 publications

Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment

Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment

A Phase 2/3 Trial of Pabinafusp Alfa, IDS Fused with Anti-Human Transferrin Receptor Antibody, Targeting Neurodegeneration in MPS-II

Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations

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