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  1. Article: Dose-dependent effects of a brain-penetrating iduronate-2-sulfatase on neurobehavioral impairments in mucopolysaccharidosis II mice.

    Morimoto, Hideto / Morioka, Hiroki / Imakiire, Atsushi / Yamamoto, Ryuji / Hirato, Tohru / Sonoda, Hiroyuki / Minami, Kohtaro

    Molecular therapy. Methods & clinical development

    2022  Volume 25, Page(s) 534–544

    Abstract: Deposition of heparan sulfate (HS) in the brain of patients with mucopolysaccharidosis II (MPS II) is believed to be the leading cause of neurodegeneration, resulting in several neurological signs and symptoms, including neurocognitive impairment. We ... ...

    Abstract Deposition of heparan sulfate (HS) in the brain of patients with mucopolysaccharidosis II (MPS II) is believed to be the leading cause of neurodegeneration, resulting in several neurological signs and symptoms, including neurocognitive impairment. We recently showed that pabinafusp alfa, a blood-brain-barrier-penetrating fusion protein consisting of iduronate-2-sulfatase and anti-human transferrin receptor antibody, stabilized learning ability by preventing the deposition of HS in the CNS of MPS II mice. We further examined the dose-dependent effect of pabinafusp alfa on neurological function in relation to its HS-reducing efficacy in a mouse model of MPS II. Long-term intravenous treatment with low (0.1 mg/kg), middle (0.5 mg/kg), and high (2.0 mg/kg) doses of the drug dose-dependently decreased HS concentration in the brain and cerebrospinal fluid (CSF). A comparable dose-dependent effect in the prevention of neuronal damage in the CNS, and dose-dependent improvements in neurobehavioral performance tests, such as gait analysis, pole test, Y maze, and Morris water maze, were also observed. Notably, the water maze test performance was inversely correlated with the HS levels in the brain and CSF. This study provides nonclinical evidence substantiating a quantitative dose-dependent relationship between HS reduction in the CNS and neurological improvements in MPS II.
    Language English
    Publishing date 2022-05-10
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2872938-9
    ISSN 2329-0501 ; 2329-0501
    ISSN (online) 2329-0501
    ISSN 2329-0501
    DOI 10.1016/j.omtm.2022.05.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Nonclinical safety evaluation of pabinafusp alfa, an anti-human transferrin receptor antibody and iduronate-2-sulfatase fusion protein, for the treatment of neuronopathic mucopolysaccharidosis type II.

    Yamamoto, Ryuji / Yoden, Eiji / Tanaka, Noboru / Kinoshita, Masafumi / Imakiire, Atsushi / Hirato, Tohru / Minami, Kohtaro

    Molecular genetics and metabolism reports

    2021  Volume 27, Page(s) 100758

    Abstract: Pabinafusp alfa is a fusion protein comprising a humanized anti-human transferrin receptor (TfR) antibody and human iduronate-2-sulfatase. It was developed as a novel modality to target central nervous system-related symptoms observed in patients with ... ...

    Abstract Pabinafusp alfa is a fusion protein comprising a humanized anti-human transferrin receptor (TfR) antibody and human iduronate-2-sulfatase. It was developed as a novel modality to target central nervous system-related symptoms observed in patients with mucopolysaccharidosis type II (MPS II, also known as Hunter syndrome). As the fusion protein contains an entire IgG1 molecule that binds TfR, there may be specific safety concerns, such as unexpected cellular toxicity due to its effector functions or its ability to inhibit iron metabolism, in addition to general safety concerns. Here, we present the comprehensive results of a nonclinical safety assessment of pabinafusp alfa. Pabinafusp alfa did not exhibit effector functions, as assessed by antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity studies in TfR-expressing hematopoietic cells. Repeat-dose toxicity studies in cynomolgus monkeys showed that pabinafusp alfa did not induce any significant toxicological changes at doses up to 30 mg/kg/week upon intravenous administration for up to 26 weeks. Interaction of transferrin with TfR was not inhibited by pabinafusp alfa, suggesting that the effect of pabinafusp alfa on the physiological iron transport system is minimal, which was confirmed by toxicity studies in cynomolgus monkeys. These findings suggest that pabinafusp alfa is expected to be safe for long-term use in individuals with MPS II.
    Language English
    Publishing date 2021-04-18
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2821908-9
    ISSN 2214-4269
    ISSN 2214-4269
    DOI 10.1016/j.ymgmr.2021.100758
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Pathogenic Roles of Heparan Sulfate and Its Use as a Biomarker in Mucopolysaccharidoses.

    Minami, Kohtaro / Morimoto, Hideto / Morioka, Hiroki / Imakiire, Atsushi / Kinoshita, Masafumi / Yamamoto, Ryuji / Hirato, Tohru / Sonoda, Hiroyuki

    International journal of molecular sciences

    2022  Volume 23, Issue 19

    Abstract: Heparan sulfate (HS) is an essential glycosaminoglycan (GAG) as a component of proteoglycans, which are present on the cell surface and in the extracellular matrix. HS-containing proteoglycans not only function as structural constituents of the basal ... ...

    Abstract Heparan sulfate (HS) is an essential glycosaminoglycan (GAG) as a component of proteoglycans, which are present on the cell surface and in the extracellular matrix. HS-containing proteoglycans not only function as structural constituents of the basal lamina but also play versatile roles in various physiological processes, including cell signaling and organ development. Thus, inherited mutations of genes associated with the biosynthesis or degradation of HS can cause various diseases, particularly those involving the bones and central nervous system (CNS). Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders involving GAG accumulation throughout the body caused by a deficiency of GAG-degrading enzymes. GAGs are stored differently in different types of MPSs. Particularly, HS deposition is observed in patients with MPS types I, II, III, and VII, all which involve progressive neuropathy with multiple CNS system symptoms. While therapies are available for certain symptoms in some types of MPSs, significant unmet medical needs remain, such as neurocognitive impairment. This review presents recent knowledge on the pathophysiological roles of HS focusing on the pathogenesis of MPSs. We also discuss the possible use and significance of HS as a biomarker for disease severity and therapeutic response in MPSs.
    MeSH term(s) Biomarkers ; Glycosaminoglycans ; Heparan Sulfate Proteoglycans ; Heparitin Sulfate/metabolism ; Humans ; Mucopolysaccharidoses/pathology ; Mucopolysaccharidosis I
    Chemical Substances Biomarkers ; Glycosaminoglycans ; Heparan Sulfate Proteoglycans ; Heparitin Sulfate (9050-30-0)
    Language English
    Publishing date 2022-10-03
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms231911724
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Transferrin Receptor-Targeted Iduronate-2-sulfatase Penetrates the Blood-Retinal Barrier and Improves Retinopathy in Mucopolysaccharidosis II Mice.

    Imakiire, Atsushi / Morimoto, Hideto / Suzuki, Hidehiko / Masuda, Tomomi / Yoden, Eiji / Inoue, Asuka / Morioka, Hiroki / Konaka, Takashi / Mori, Ayaka / Shirasaka, Ryoji / Kato, Ryo / Hirato, Tohru / Sonoda, Hiroyuki / Minami, Kohtaro

    Molecular pharmaceutics

    2023  Volume 20, Issue 11, Page(s) 5901–5909

    Abstract: Mucopolysaccharidoses (MPSs) make up a group of lysosomal storage diseases characterized by the aberrant accumulation of glycosaminoglycans throughout the body. Patients with MPSs display various signs and symptoms, such as retinopathy, which is also ... ...

    Abstract Mucopolysaccharidoses (MPSs) make up a group of lysosomal storage diseases characterized by the aberrant accumulation of glycosaminoglycans throughout the body. Patients with MPSs display various signs and symptoms, such as retinopathy, which is also observed in patients with MPS II. Unfortunately, retinal disorders in MPS II are resistant to conventional intravenous enzyme-replacement therapy because the blood-retinal barrier (BRB) impedes drug penetration. In this study, we show that a fusion protein, designated pabinafusp alfa, consisting of an antihuman transferrin receptor antibody and iduronate-2-sulfatase (IDS), crosses the BRB and reaches the retina in a murine model of MPS II. We found that retinal function, as assessed by electroretinography (ERG) in MPS II mice, deteriorated with age. Early intervention with repeated intravenous treatment of pabinafusp alfa decreased heparan sulfate deposition in the retina, optic nerve, and visual cortex, thus preserving or even improving the ERG response in MPS II mice. Histological analysis further revealed that pabinafusp alfa mitigated the loss of the photoreceptor layer observed in diseased mice. In contrast, recombinant nonfused IDS failed to reach the retina and hardly affected the retinal disease. These results support the hypothesis that transferrin receptor-targeted IDS can penetrate the BRB, thereby ameliorating retinal dysfunction in MPS II.
    MeSH term(s) Animals ; Mice ; Blood-Retinal Barrier/metabolism ; Glycosaminoglycans ; Iduronate Sulfatase/metabolism ; Iduronate Sulfatase/therapeutic use ; Iduronic Acid ; Mucopolysaccharidosis II/drug therapy ; Mucopolysaccharidosis II/diagnosis ; Receptors, Transferrin ; Retinal Diseases/drug therapy
    Chemical Substances Glycosaminoglycans ; Iduronate Sulfatase (EC 3.1.6.13) ; Iduronic Acid (3402-98-0) ; Receptors, Transferrin ; Ids protein, mouse (EC 3.1.6.13) ; Tfrc protein, mouse
    Language English
    Publishing date 2023-10-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2138405-8
    ISSN 1543-8392 ; 1543-8384
    ISSN (online) 1543-8392
    ISSN 1543-8384
    DOI 10.1021/acs.molpharmaceut.3c00736
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6250: Show issues Location:
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  5. Article: Enzyme replacement with transferrin receptor-targeted α-L-iduronidase rescues brain pathology in mucopolysaccharidosis I mice.

    Kida, Sachiho / Koshimura, Yuri / Yoden, Eiji / Yoshioka, Aya / Morimoto, Hideto / Imakiire, Atsushi / Tanaka, Noboru / Tanaka, Satowa / Mori, Ayaka / Ito, Jun / Inoue, Asuka / Yamamoto, Ryuji / Minami, Kohtaro / Hirato, Tohru / Takahashi, Kenichi / Sonoda, Hiroyuki

    Molecular therapy. Methods & clinical development

    2023  Volume 29, Page(s) 439–449

    Abstract: Mucopolysaccharidosis I (MPS I), a lysosomal storage disease caused by dysfunction of α-L-iduronidase (IDUA), is characterized by the deposition of dermatan sulfate (DS) and heparan sulfate (HS) throughout the body, which causes several somatic and ... ...

    Abstract Mucopolysaccharidosis I (MPS I), a lysosomal storage disease caused by dysfunction of α-L-iduronidase (IDUA), is characterized by the deposition of dermatan sulfate (DS) and heparan sulfate (HS) throughout the body, which causes several somatic and central nervous symptoms. Although enzyme-replacement therapy (ERT) is currently available to treat MPS I, it does not alleviate central nervous disorders, as it cannot penetrate the blood-brain barrier. Here we evaluate the brain delivery, efficacy, and safety of JR-171, a fusion protein comprising humanized anti-human transferrin receptor antibody Fab and IDUA, using monkeys and MPS I mice. Intravenously administered JR-171 was distributed in major organs, including the brain, and reduced DS and HS concentrations in the central nervous system and peripheral tissues. JR-171 exerted similar effects on peripheral disorders similar to conventional ERT and further reversed brain pathology in MPS I mice. We found that JR-171 improved spatial learning ability, which was seen to deteriorate in the vehicle-treated mice. Further, no safety concerns were noted in repeat-dose toxicity studies in monkeys. This study provides nonclinical evidence that JR-171 might potentially prevent and even improve disease conditions in patients with neuronopathic MPS I without serious safety concerns.
    Language English
    Publishing date 2023-05-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2872938-9
    ISSN 2329-0501 ; 2329-0501
    ISSN (online) 2329-0501
    ISSN 2329-0501
    DOI 10.1016/j.omtm.2023.05.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 7107: Show issues Location:
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