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  1. 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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  2. 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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  3. Article ; Online: Evaluation of cerebrospinal fluid heparan sulfate as a biomarker of neuropathology in a murine model of mucopolysaccharidosis type II using high-sensitivity LC/MS/MS.

    Tanaka, Noboru / Kida, Sachiho / Kinoshita, Masafumi / Morimoto, Hideto / Shibasaki, Tadao / Tachibana, Katsuhiko / Yamamoto, Ryuji

    Molecular genetics and metabolism

    2018  Volume 125, Issue 1-2, Page(s) 53–58

    Abstract: Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS), an enzyme that catabolizes glycosaminoglycans (GAGs) including heparan sulfate (HS) and dermatan sulfate (DS). ...

    Abstract Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS), an enzyme that catabolizes glycosaminoglycans (GAGs) including heparan sulfate (HS) and dermatan sulfate (DS). GAG accumulation leads to severe neurological and somatic impairments. At present, the most common treatment for MPS II is intravenous enzyme replacement therapy; however, the inability of recombinant IDS to cross the blood-brain barrier (BBB) restricts therapeutic efficacy for neurological manifestations. We recently developed a BBB-penetrating IDS fusion protein, JR-141, and demonstrated its ability to reduce GAG accumulation in the brain of human transferrin receptor knock-in and Ids knock-out mice (TFRC-KI/Ids-KO), an animal model of MPS II, following intravenous administration. Given the impossibility of measuring GAG accumulation in the brains of human patients with MPS II, we hypothesized that GAG content in the cerebrospinal fluid (CSF) might serve as an indicator of brain GAG burden. To test this hypothesis, we optimized a high-sensitivity method for quantifying HS and DS in low-volume samples by combining acidic methanolysis and liquid chromatography-tandem mass spectrometry (LC/MS/MS). We employed this method to quantify HS and DS in samples from TFRC-KI/Ids-KO mice and revealed that HS but not DS accumulated in the central nerve system (CNS). Moreover, concentrations of HS in CSF correlated with those in brain. Finally, intravenous treatment with JR-141 reduced levels of HS in the CSF and brain in TFRC-KI/Ids-KO mice. These results suggest that CSF HS content may be a useful biomarker for evaluating the brain GAG accumulation and the therapeutic efficacy of drugs in patients with MPS II.
    MeSH term(s) Animals ; Biomarkers/cerebrospinal fluid ; Blood-Brain Barrier/drug effects ; Brain/drug effects ; Brain/metabolism ; Brain/pathology ; Chromatography, Liquid ; Dermatan Sulfate/cerebrospinal fluid ; Disease Models, Animal ; Heparitin Sulfate/cerebrospinal fluid ; Heparitin Sulfate/genetics ; Humans ; Iduronate Sulfatase/genetics ; Mice ; Mice, Knockout ; Mucopolysaccharidosis II/cerebrospinal fluid ; Mucopolysaccharidosis II/drug therapy ; Mucopolysaccharidosis II/genetics ; Mucopolysaccharidosis II/pathology ; Nervous System Diseases/cerebrospinal fluid ; Nervous System Diseases/pathology ; Receptors, Transferrin/genetics ; Tandem Mass Spectrometry
    Chemical Substances Biomarkers ; Receptors, Transferrin ; Tfrc protein, mouse ; Dermatan Sulfate (24967-94-0) ; Heparitin Sulfate (9050-30-0) ; Iduronate Sulfatase (EC 3.1.6.13)
    Language English
    Publishing date 2018-07-23
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1418518-0
    ISSN 1096-7206 ; 1096-7192
    ISSN (online) 1096-7206
    ISSN 1096-7192
    DOI 10.1016/j.ymgme.2018.07.013
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 617: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Clearance of heparan sulfate in the brain prevents neurodegeneration and neurocognitive impairment in MPS II mice.

    Morimoto, Hideto / Kida, Sachiho / Yoden, Eiji / Kinoshita, Masafumi / Tanaka, Noboru / Yamamoto, Ryuji / Koshimura, Yuri / Takagi, Haruna / Takahashi, Kenichi / Hirato, Tohru / Minami, Kohtaro / Sonoda, Hiroyuki

    Molecular therapy : the journal of the American Society of Gene Therapy

    2021  Volume 29, Issue 5, Page(s) 1853–1861

    Abstract: Mucopolysaccharidosis II (MPS II), a lysosomal storage disease caused by mutations in iduronate-2-sulfatase (IDS), is characterized by a wide variety of somatic and neurologic symptoms. The currently approved intravenous enzyme replacement therapy with ... ...

    Abstract Mucopolysaccharidosis II (MPS II), a lysosomal storage disease caused by mutations in iduronate-2-sulfatase (IDS), is characterized by a wide variety of somatic and neurologic symptoms. The currently approved intravenous enzyme replacement therapy with recombinant IDS (idursulfase) is ineffective for CNS manifestations due to its inability to cross the blood-brain barrier (BBB). Here, we demonstrate that the clearance of heparan sulfate (HS) deposited in the brain by a BBB-penetrable antibody-enzyme fusion protein prevents neurodegeneration and neurocognitive dysfunctions in MPS II mice. The fusion protein pabinafusp alfa was chronically administered intravenously to MPS II mice. The drug reduced HS and attenuated histopathological changes in the brain, as well as in peripheral tissues. The loss of spatial learning abilities was completely suppressed by pabinafusp alfa, but not by idursulfase, indicating an association between HS deposition in the brain, neurodegeneration, and CNS manifestations in these mice. Furthermore, HS concentrations in the brain and reduction thereof by pabinafusp alpha correlated with those in the cerebrospinal fluid (CSF). Thus, repeated intravenous administration of pabinafusp alfa to MPS II mice decreased HS deposition in the brain, leading to prevention of neurodegeneration and maintenance of neurocognitive function, which may be predicted from HS concentrations in CSF.
    MeSH term(s) Administration, Intravenous ; Animals ; Antibodies/genetics ; Blood-Brain Barrier ; Brain/drug effects ; Brain/metabolism ; Disease Models, Animal ; Glycoproteins/genetics ; Heparitin Sulfate/cerebrospinal fluid ; Heparitin Sulfate/metabolism ; Humans ; Iduronate Sulfatase/administration & dosage ; Iduronate Sulfatase/pharmacology ; Immunoglobulin G/chemistry ; Immunoglobulin G/genetics ; Mice ; Mucopolysaccharidosis II/cerebrospinal fluid ; Mucopolysaccharidosis II/drug therapy ; Mucopolysaccharidosis II/psychology ; Neurocognitive Disorders/etiology ; Neurocognitive Disorders/prevention & control ; Receptors, Transferrin/antagonists & inhibitors ; Recombinant Fusion Proteins/administration & dosage ; Recombinant Fusion Proteins/pharmacology ; Recombinant Proteins/administration & dosage ; Recombinant Proteins/genetics ; Recombinant Proteins/pharmacology ; Spatial Learning/drug effects
    Chemical Substances Antibodies ; Glycoproteins ; IDS protein, human ; Immunoglobulin G ; Receptors, Transferrin ; Recombinant Fusion Proteins ; Recombinant Proteins ; Heparitin Sulfate (9050-30-0) ; Iduronate Sulfatase (EC 3.1.6.13) ; idursulfase (EC 3.1.6.13)
    Language English
    Publishing date 2021-01-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2010592-7
    ISSN 1525-0024 ; 1525-0016
    ISSN (online) 1525-0024
    ISSN 1525-0016
    DOI 10.1016/j.ymthe.2021.01.027
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5640: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: A Blood-Brain-Barrier-Penetrating Anti-human Transferrin Receptor Antibody Fusion Protein for Neuronopathic Mucopolysaccharidosis II.

    Sonoda, Hiroyuki / Morimoto, Hideto / Yoden, Eiji / Koshimura, Yuri / Kinoshita, Masafumi / Golovina, Galina / Takagi, Haruna / Yamamoto, Ryuji / Minami, Kohtaro / Mizoguchi, Akira / Tachibana, Katsuhiko / Hirato, Tohru / Takahashi, Kenichi

    Molecular therapy : the journal of the American Society of Gene Therapy

    2018  Volume 26, Issue 5, Page(s) 1366–1374

    Abstract: Mucopolysaccharidosis II (MPS II) is an X-linked recessive lysosomal storage disease caused by mutations in the iduronate-2-sulfatase (IDS) gene. Since IDS catalyzes the degradation of glycosaminoglycans (GAGs), deficiency in this enzyme leads to ... ...

    Abstract Mucopolysaccharidosis II (MPS II) is an X-linked recessive lysosomal storage disease caused by mutations in the iduronate-2-sulfatase (IDS) gene. Since IDS catalyzes the degradation of glycosaminoglycans (GAGs), deficiency in this enzyme leads to accumulation of GAGs in most cells in all tissues and organs, resulting in severe somatic and neurological disorders. Although enzyme replacement therapy with human IDS (hIDS) has been used for the treatment of MPS II, this therapy is not effective for defects in the CNS mainly because the enzyme cannot cross the blood-brain barrier (BBB). Here, we developed a BBB-penetrating fusion protein, JR-141, which consists of an anti-human transferrin receptor (hTfR) antibody and intact hIDS. The TfR-mediated incorporation of JR-141 was confirmed by using human fibroblasts in vitro. When administrated intravenously to hTfR knockin mice or monkeys, JR-141, but not naked hIDS, was detected in the brain. In addition, the intravenous administration of JR-141 reduced the accumulation of GAGs both in the peripheral tissues and in the brain of hTfR knockin mice lacking Ids, an animal model of MPS II. These data provide a proof of concept for the translation of JR-141 to clinical study for the treatment of patients with MPS II with CNS disorders.
    MeSH term(s) Animals ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/pharmacokinetics ; Antibodies, Monoclonal/pharmacology ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Brain/drug effects ; Brain/metabolism ; Cell Line ; Disease Models, Animal ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Humans ; Mice ; Mice, Knockout ; Mucopolysaccharidosis II/drug therapy ; Mucopolysaccharidosis II/genetics ; Mucopolysaccharidosis II/metabolism ; Receptor, IGF Type 2/genetics ; Receptor, IGF Type 2/metabolism ; Receptors, Transferrin/antagonists & inhibitors ; Recombinant Fusion Proteins ; Tissue Distribution/drug effects
    Chemical Substances Antibodies, Monoclonal ; Receptor, IGF Type 2 ; Receptors, Transferrin ; Recombinant Fusion Proteins ; cation-dependent mannose-6-phosphate receptor
    Language English
    Publishing date 2018-03-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2010592-7
    ISSN 1525-0024 ; 1525-0016
    ISSN (online) 1525-0024
    ISSN 1525-0016
    DOI 10.1016/j.ymthe.2018.02.032
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5640: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  6. Article ; Online: Orally administered phosphatidic acids and lysophosphatidic acids ameliorate aspirin-induced stomach mucosal injury in mice.

    Tanaka, Tamotsu / Morito, Katsuya / Kinoshita, Masafumi / Ohmoto, Mayumi / Urikura, Mai / Satouchi, Kiyoshi / Tokumura, Akira

    Digestive diseases and sciences

    2012  Volume 58, Issue 4, Page(s) 950–958

    Abstract: Background: Recent investigations revealed that lysophosphatidic acid (LPA), a phospholipid with a growth factor-like activity, plays an important role in the integrity of the gastrointestinal tract epithelium.: Aim: This paper attempts to clarify ... ...

    Abstract Background: Recent investigations revealed that lysophosphatidic acid (LPA), a phospholipid with a growth factor-like activity, plays an important role in the integrity of the gastrointestinal tract epithelium.
    Aim: This paper attempts to clarify the effect of orally administered phosphatidic acid (PA) and LPA on aspirin-induced gastric lesions in mice.
    Materials and methods: Phospholipids, a free fatty acid, a diacylglycerol and a triglyceride at 1 mM (5.7 μmol/kg body weight) or 0.1 mM were orally administered to mice 0.5 h before oral administration of aspirin (1.7 mmol/kg). The total length of lesions formed on the stomach wall was measured as a lesion index. Formation of LPA from PA in the mouse stomach was examined by in vitro (in stomach lavage fluid), ex vivo (in an isolated stomach) and in vivo (in the stomach of a living mouse) examinations of phospholipase activity.
    Results: Palmitic acid, dioleoyl-glycerol, olive oil and lysophosphatidylcholine did not affect the aspirin-induced lesions. In contrast, phosphatidylcholine (1 mM), LPA (1 mM) and PA (0.1, 1 mM) significantly reduced the lesion index. Evidence for formation of LPA from PA in the stomach by gastric phospholipase A2 was obtained by in vitro, ex vivo and in vivo experiments. An LPA-specific receptor, LPA2, was found to be localized on the gastric surface-lining cells of mice.
    Conclusion: Pretreatment with PA-rich diets may prevent nonsteroidal anti-inflammatory drug-induced stomach ulcers.
    MeSH term(s) Administration, Oral ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/adverse effects ; Aspirin/adverse effects ; Drug Evaluation, Preclinical ; In Vitro Techniques ; Lysophospholipids/metabolism ; Lysophospholipids/therapeutic use ; Male ; Mice ; Mice, Inbred ICR ; Phosphatidic Acids/metabolism ; Phosphatidic Acids/therapeutic use ; Phospholipases A2/metabolism ; Receptors, Lysophosphatidic Acid/metabolism ; Stomach/enzymology ; Stomach Ulcer/chemically induced ; Stomach Ulcer/prevention & control
    Chemical Substances Anti-Inflammatory Agents, Non-Steroidal ; Lysophospholipids ; Phosphatidic Acids ; Receptors, Lysophosphatidic Acid ; Phospholipases A2 (EC 3.1.1.4) ; lysophosphatidic acid (PG6M3969SG) ; Aspirin (R16CO5Y76E)
    Language English
    Publishing date 2012-11-18
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 304250-9
    ISSN 1573-2568 ; 0163-2116
    ISSN (online) 1573-2568
    ISSN 0163-2116
    DOI 10.1007/s10620-012-2475-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Ui V Zs.35: Show issues Location:
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