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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
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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
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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
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Zs.A 6250: Show issues

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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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Zs.A 7107: Show issues

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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
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Zs.A 617: Show issues

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Article ; Online: Autophagy in the Central Nervous System and Effects of Chloroquine in Mucopolysaccharidosis Type II Mice.

Maeda, Mitsuyo / Seto, Toshiyuki / Kadono, Chiho / Morimoto, Hideto / Kida, Sachiho / Suga, Mitsuo / Nakamura, Motohiro / Kataoka, Yosky / Hamazaki, Takashi / Shintaku, Haruo

International journal of molecular sciences

2019 Volume 20, Issue 23

Abstract: Mucopolysaccharidosis type II (MPS II) is a rare lysosomal storage disease (LSD) involving a genetic error in iduronic acid-2-sulfatase (IDS) metabolism that leads to accumulation of glycosaminoglycans within intracellular lysosomes. The primary ... ...

Abstract	Mucopolysaccharidosis type II (MPS II) is a rare lysosomal storage disease (LSD) involving a genetic error in iduronic acid-2-sulfatase (IDS) metabolism that leads to accumulation of glycosaminoglycans within intracellular lysosomes. The primary treatment for MPS II, enzyme replacement therapy, is not effective for central nervous system (CNS) symptoms, such as intellectual disability, because the drugs do not cross the blood-brain barrier. Recently, autophagy has been associated with LSDs. In this study, we examined the morphologic relationship between neuronal damage and autophagy in IDS knockout mice using antibodies against subunit c of mitochondrial adenosine triphosphate (ATP) synthetase and p62. Immunohistological changes suggesting autophagy, such as vacuolation, were observed in neurons, microglia, and pericytes throughout the CNS, and the numbers increased over postnatal development. Oral administration of chloroquine, which inhibits autophagy, did not suppress damage to microglia and pericytes, but greatly reduced neuronal vacuolation and eliminated neuronal cells with abnormal inclusions. Thus, decreasing autophagy appears to prevent neuronal degeneration. These results suggest that an autophagy modulator could be used in addition to conventional enzyme replacement therapy to preserve the CNS in patients with MPS II.
MeSH term(s)	Animals ; Autophagy ; Brain/metabolism ; Brain/pathology ; Chloroquine/pharmacology ; Iduronate Sulfatase/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Microglia/drug effects ; Microglia/metabolism ; Microglia/ultrastructure ; Mitochondrial Proton-Translocating ATPases/genetics ; Mitochondrial Proton-Translocating ATPases/metabolism ; Mucopolysaccharidosis II/metabolism ; Mucopolysaccharidosis II/pathology ; Neurons/drug effects ; Neurons/metabolism ; Neurons/ultrastructure ; Sequestosome-1 Protein/genetics ; Sequestosome-1 Protein/metabolism
Chemical Substances	Sequestosome-1 Protein ; Chloroquine (886U3H6UFF) ; Ids protein, mouse (EC 3.1.6.13) ; Iduronate Sulfatase (EC 3.1.6.13) ; Mitochondrial Proton-Translocating ATPases (EC 3.6.3.-)
Language	English
Publishing date	2019-11-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms20235829
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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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Zs.A 5640: Show issues

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Article ; Online: Non-clinical evaluation of JR-051 as a biosimilar to agalsidase beta for the treatment of Fabry disease.

Morimoto, Hideto / Ito, Yae / Yoden, Eiji / Horie, Masato / Tanaka, Noboru / Komurasaki, Yoshikazu / Yamamoto, Ryuji / Mihara, Kazutoshi / Minami, Kohtaro / Hirato, Tohru

Molecular genetics and metabolism

2018 Volume 125, Issue 1-2, Page(s) 153–160

Abstract: Fabry disease (FD) is an X-linked lysosomal storage disease. It is caused by deficiency of the enzyme α-galactosidase A (α-Gal A), which leads to excessive deposition of neutral glycosphingolipids, especially globotriaosylceramide (GL-3), in cells ... ...

Abstract	Fabry disease (FD) is an X-linked lysosomal storage disease. It is caused by deficiency of the enzyme α-galactosidase A (α-Gal A), which leads to excessive deposition of neutral glycosphingolipids, especially globotriaosylceramide (GL-3), in cells throughout the body. Progressive accumulation of GL-3 causes life-threatening complications in several tissues and organs, including the vasculature, heart, and kidney. Currently available enzyme replacement therapy for FD employs recombinant α-Gal A in two formulations, namely agalsidase alfa and agalsidase beta. Here, we evaluated JR-051 as a biosimilar to agalsidase beta in a non-clinical study. JR-051 was shown to have identical primary and similar higher-order structures to agalsidase beta. Mannose-6-phosphate content was higher in JR-051 than in agalsidase beta, which probably accounts for a slightly better uptake into fibroblasts in vitro. In spite of these differences in in vitro biological features, pharmacokinetic profiles of the two compounds in mice, rats, and monkeys were similar. The ability to reduce GL-3 accumulation in the kidney, heart, skin, liver, spleen, and plasma of Gla-knockout mice, a model of FD, was not different between JR-051 and agalsidase beta. Furthermore, we identified no safety concerns regarding JR-051 in a 13-week evaluation using cynomolgus monkeys. These findings indicate that JR-051 is similar to agalsidase beta in terms of physicochemical and biological properties.
MeSH term(s)	Animals ; Biosimilar Pharmaceuticals/administration & dosage ; Enzyme Replacement Therapy ; Fabry Disease/drug therapy ; Fabry Disease/genetics ; Fabry Disease/pathology ; Fibroblasts ; Humans ; Isoenzymes/administration & dosage ; Isoenzymes/genetics ; Kidney/metabolism ; Kidney/pathology ; Liver/metabolism ; Liver/pathology ; Male ; Mice ; Mice, Knockout ; Skin/metabolism ; Skin/pathology ; Spleen/metabolism ; Spleen/pathology ; Trihexosylceramides ; alpha-Galactosidase/administration & dosage ; alpha-Galactosidase/genetics
Chemical Substances	Biosimilar Pharmaceuticals ; Isoenzymes ; Trihexosylceramides ; globotriaosylceramide (71965-57-6) ; alpha-Galactosidase (EC 3.2.1.22) ; agalsidase beta (RZD65TSM9U)
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.2018.07.009
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Article ; Online: Enzyme Replacement Therapy with Pabinafusp Alfa for Neuronopathic Mucopolysaccharidosis II: An Integrated Analysis of Preclinical and Clinical Data.

Giugliani, Roberto / Martins, Ana Maria / Okuyama, Torayuki / Eto, Yoshikatsu / Sakai, Norio / Nakamura, Kimitoshi / Morimoto, Hideto / Minami, Kohtaro / Yamamoto, Tatsuyoshi / Yamaoka, Mariko / Ikeda, Toshiaki / So, Sairei / Tanizawa, Kazunori / Sonoda, Hiroyuki / Schmidt, Mathias / Sato, Yuji

International journal of molecular sciences

2021 Volume 22, Issue 20

Abstract: Enzyme replacement therapy (ERT) improves somatic manifestations in mucopolysaccharidoses (MPS). However, because intravenously administered enzymes cannot cross the blood-brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration ... ...

Abstract	Enzyme replacement therapy (ERT) improves somatic manifestations in mucopolysaccharidoses (MPS). However, because intravenously administered enzymes cannot cross the blood-brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT in order to achieve CNS effects, but the burdens on patients are inimical to long-term administrations. However, since pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in a mouse model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT that is effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the previously obtained preclinical and clinical evidence related to the use of this drug, presents latest data, and discusses the preclinical, translational, and clinical challenges of evaluating, ameliorating, and preventing neurodegeneration in patients with MPS-II.
MeSH term(s)	Animals ; Biomarkers/cerebrospinal fluid ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Clinical Trials as Topic ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Enzyme Replacement Therapy ; Humans ; Iduronate Sulfatase/genetics ; Iduronate Sulfatase/metabolism ; Iduronate Sulfatase/therapeutic use ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mucopolysaccharidosis II/drug therapy ; Mucopolysaccharidosis II/pathology ; Recombinant Proteins/adverse effects ; Recombinant Proteins/pharmacology ; Recombinant Proteins/therapeutic use ; Severity of Illness Index
Chemical Substances	Biomarkers ; Recombinant Proteins ; Iduronate Sulfatase (EC 3.1.6.13)
Language	English
Publishing date	2021-10-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms222010938
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Article: Insectivory by Five Sympatric Carnivores in Cool-Temperate Deciduous Forests

Koike, Shinsuke / Morimoto Hideto / Goto Yusuke / Kozakai Chinatsu / Yamazaki Koji

Mammal study. 2012 June, v. 37, no. 2

2012

Abstract: We studied insectivory by five carnivoresâthe Asiatic black bear (Ursus thibetanus), Japanese marten (Martes melampus), Japanese badger (Meles meles), red fox (Vulpes vulpes), and raccoon dog (Nyctereutes procyonoides)âin a cool-temperate deciduous ... ...

Abstract	We studied insectivory by five carnivoresâthe Asiatic black bear (Ursus thibetanus), Japanese marten (Martes melampus), Japanese badger (Meles meles), red fox (Vulpes vulpes), and raccoon dog (Nyctereutes procyonoides)âin a cool-temperate deciduous forest in Japan. From May 2003 to April 2005, we assayed 373 fecal samples (91 from bear, 158 from marten, 43 from badger, 36 from fox, and 45 from raccoon dog) for insects. Each carnivore species consumed a variety of insect species, some preferentially. Bears preferred colonial insects like ants and wasps; martens ate a variety of forest insects, such as ground beetles and arboreal insects; badgers preferred forest ground beetles; foxes ate ground beetles and grassland insects; and raccoon dogs ate a variety of species. Dietary preferences may reflect the feeding strategy, behavior, or habitat preference of each carnivore species. Based on the habitat preferences of the insects, we could assign carnivores to particular microhabitats: bears and martens used forest in three dimensions, badgers inhabited forest in two dimensions, foxes used grassland and forest in two dimensions, and raccoon dogs inhabited grassland and forest in three dimensions. Identification of insects in feces may provide information on the dietary and habitat preferences of these carnivores.
Keywords	Carabidae ; Formicidae ; Martes ; Meles meles ; Nyctereutes procyonoides ; Ursus thibetanus ; Vulpes vulpes ; badgers ; deciduous forests ; feces ; feeding methods ; forest insects ; foxes ; grasslands ; habitat preferences ; insectivores ; microhabitats ; diet ; fecal analysis ; food habits ; insect ; predator ; Japan
Language	English
Dates of publication	2012-06
Size	p. 73-83.
Publishing place	UniBio Press
Document type	Article
ZDB-ID	2152177-3
ISSN	1348-6160 ; 1343-4152
ISSN (online)	1348-6160
ISSN	1343-4152
DOI	10.3106%2F041.037.0208
Database	NAL-Catalogue (AGRICOLA)

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