AAV expression of a blood-brain barrier-penetrating form of β-galactosidase normalises GM1 ganglioside storage in mice

Saki Kondo Matsushima; Yohta Shimada; Masafumi Kinoshita; Takashi Nagashima; Shinichiro Okamoto; Sayoko Iizuka; Haruna Takagi; Shunsuke Iizuka; Takashi Higuchi; Hiroyuki Hioki; Ayako M. Watabe; Hiroyuki Sonoda; Toya Ohashi; Hiroshi Kobayashi

doi:10.1172/JCI180724

¹Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan

²Research Division, JCR Pharmaceuticals, Kobe, Japan

³Institute of Clinical Medicine and Research, Research Center for Medical Sc, The Jikei University School of Medicine, Chiba, Japan

⁴Department of Neuroanatomy, Juntendo University Graduate School of Medicine, Tokyo, Japan

⁵Department of Human Health Science and Therapeutics, The Jikei University of School of Nursing, Tokyo, Japan

Find articles by Matsushima, S. in: JCI | PubMed | Google Scholar

¹Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan

²Research Division, JCR Pharmaceuticals, Kobe, Japan

³Institute of Clinical Medicine and Research, Research Center for Medical Sc, The Jikei University School of Medicine, Chiba, Japan

⁴Department of Neuroanatomy, Juntendo University Graduate School of Medicine, Tokyo, Japan

⁵Department of Human Health Science and Therapeutics, The Jikei University of School of Nursing, Tokyo, Japan

Find articles by Shimada, Y. in: JCI | PubMed | Google Scholar

¹Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan

²Research Division, JCR Pharmaceuticals, Kobe, Japan

³Institute of Clinical Medicine and Research, Research Center for Medical Sc, The Jikei University School of Medicine, Chiba, Japan

⁴Department of Neuroanatomy, Juntendo University Graduate School of Medicine, Tokyo, Japan

⁵Department of Human Health Science and Therapeutics, The Jikei University of School of Nursing, Tokyo, Japan

Find articles by Kinoshita, M. in: JCI | PubMed | Google Scholar

¹Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan

²Research Division, JCR Pharmaceuticals, Kobe, Japan

³Institute of Clinical Medicine and Research, Research Center for Medical Sc, The Jikei University School of Medicine, Chiba, Japan

⁴Department of Neuroanatomy, Juntendo University Graduate School of Medicine, Tokyo, Japan

⁵Department of Human Health Science and Therapeutics, The Jikei University of School of Nursing, Tokyo, Japan

Find articles by Nagashima, T. in: JCI | PubMed | Google Scholar

¹Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan

²Research Division, JCR Pharmaceuticals, Kobe, Japan

³Institute of Clinical Medicine and Research, Research Center for Medical Sc, The Jikei University School of Medicine, Chiba, Japan

⁴Department of Neuroanatomy, Juntendo University Graduate School of Medicine, Tokyo, Japan

⁵Department of Human Health Science and Therapeutics, The Jikei University of School of Nursing, Tokyo, Japan

Find articles by Okamoto, S. in: JCI | PubMed | Google Scholar

¹Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan

²Research Division, JCR Pharmaceuticals, Kobe, Japan

³Institute of Clinical Medicine and Research, Research Center for Medical Sc, The Jikei University School of Medicine, Chiba, Japan

⁴Department of Neuroanatomy, Juntendo University Graduate School of Medicine, Tokyo, Japan

⁵Department of Human Health Science and Therapeutics, The Jikei University of School of Nursing, Tokyo, Japan

Find articles by Iizuka, S. in: JCI | PubMed | Google Scholar

¹Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan

²Research Division, JCR Pharmaceuticals, Kobe, Japan

³Institute of Clinical Medicine and Research, Research Center for Medical Sc, The Jikei University School of Medicine, Chiba, Japan

⁴Department of Neuroanatomy, Juntendo University Graduate School of Medicine, Tokyo, Japan

⁵Department of Human Health Science and Therapeutics, The Jikei University of School of Nursing, Tokyo, Japan

Find articles by Takagi, H. in: JCI | PubMed | Google Scholar

¹Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan

²Research Division, JCR Pharmaceuticals, Kobe, Japan

³Institute of Clinical Medicine and Research, Research Center for Medical Sc, The Jikei University School of Medicine, Chiba, Japan

⁴Department of Neuroanatomy, Juntendo University Graduate School of Medicine, Tokyo, Japan

⁵Department of Human Health Science and Therapeutics, The Jikei University of School of Nursing, Tokyo, Japan

Find articles by Iizuka, S. in: JCI | PubMed | Google Scholar

¹Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan

²Research Division, JCR Pharmaceuticals, Kobe, Japan

³Institute of Clinical Medicine and Research, Research Center for Medical Sc, The Jikei University School of Medicine, Chiba, Japan

⁴Department of Neuroanatomy, Juntendo University Graduate School of Medicine, Tokyo, Japan

⁵Department of Human Health Science and Therapeutics, The Jikei University of School of Nursing, Tokyo, Japan

Find articles by Higuchi, T. in: JCI | PubMed | Google Scholar

¹Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan

²Research Division, JCR Pharmaceuticals, Kobe, Japan

³Institute of Clinical Medicine and Research, Research Center for Medical Sc, The Jikei University School of Medicine, Chiba, Japan

⁴Department of Neuroanatomy, Juntendo University Graduate School of Medicine, Tokyo, Japan

⁵Department of Human Health Science and Therapeutics, The Jikei University of School of Nursing, Tokyo, Japan

Find articles by Hioki, H. in: JCI | PubMed | Google Scholar

¹Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan

²Research Division, JCR Pharmaceuticals, Kobe, Japan

³Institute of Clinical Medicine and Research, Research Center for Medical Sc, The Jikei University School of Medicine, Chiba, Japan

⁴Department of Neuroanatomy, Juntendo University Graduate School of Medicine, Tokyo, Japan

⁵Department of Human Health Science and Therapeutics, The Jikei University of School of Nursing, Tokyo, Japan

Find articles by Watabe, A. in: JCI | PubMed | Google Scholar

¹Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan

²Research Division, JCR Pharmaceuticals, Kobe, Japan

³Institute of Clinical Medicine and Research, Research Center for Medical Sc, The Jikei University School of Medicine, Chiba, Japan

⁴Department of Neuroanatomy, Juntendo University Graduate School of Medicine, Tokyo, Japan

⁵Department of Human Health Science and Therapeutics, The Jikei University of School of Nursing, Tokyo, Japan

Find articles by Sonoda, H. in: JCI | PubMed | Google Scholar

¹Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan

²Research Division, JCR Pharmaceuticals, Kobe, Japan

³Institute of Clinical Medicine and Research, Research Center for Medical Sc, The Jikei University School of Medicine, Chiba, Japan

⁴Department of Neuroanatomy, Juntendo University Graduate School of Medicine, Tokyo, Japan

⁵Department of Human Health Science and Therapeutics, The Jikei University of School of Nursing, Tokyo, Japan

Find articles by Ohashi, T. in: JCI | PubMed | Google Scholar

¹Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan

²Research Division, JCR Pharmaceuticals, Kobe, Japan

³Institute of Clinical Medicine and Research, Research Center for Medical Sc, The Jikei University School of Medicine, Chiba, Japan

⁴Department of Neuroanatomy, Juntendo University Graduate School of Medicine, Tokyo, Japan

⁵Department of Human Health Science and Therapeutics, The Jikei University of School of Nursing, Tokyo, Japan

Find articles by Kobayashi, H. in: JCI | PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI180724.
Copyright © 2025, Matsushima et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published April 8, 2025 - Version history

GM1 gangliosidosis is a lysosomal storage disorder (LSD) and caused by genetic defects in the lysosomal β-galactosidase (β-gal). The primary substrate of the β-gal is GM1 ganglioside (GM1), a sialylated glycosphingolipid abundant in the central nervous system (CNS). β-gal deficiency causes GM1 to accumulate in neural cells leading to a rapid decline in psychomotor functions, seizures, and premature death. There is currently no therapy available. Although enzyme replacement therapy (ERT) has been approved for other LSDs, its effects on the CNS are limited owing to the blood-brain barrier (BBB). Here, we assessed the therapeutic efficacy of a systemic infusion of an AAV vector carrying a gene expressing a BBB-penetrable enzyme under the control of a liver-specific promotor in GM1 gangliosidosis model mice. The BBB-penetrable enzyme consisted of the variable region of the anti-transferrin receptor-antibody fused with β-gal. The BBB-penetrable enzyme was only produced in the liver and secreted into the blood, which was efficiently distributed to various organs, including the brain. GM1 accumulation in the CNS was completely normalised, with improved neurological functions and animal survival. This therapeutic approach is expected to be applied for the treatment of several hereditary neurological diseases with CNS involvement.

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AAV expression of a blood-brain barrier-penetrating form of β-galactosidase normalises GM1 ganglioside storage in mice

Saki Kondo Matsushima,¹ Yohta Shimada,¹ Masafumi Kinoshita,² Takashi Nagashima,³ Shinichiro Okamoto,⁴ Sayoko Iizuka,¹ Haruna Takagi,² Shunsuke Iizuka,² Takashi Higuchi,¹ Hiroyuki Hioki,⁴ Ayako M. Watabe,³ Hiroyuki Sonoda,² Toya Ohashi,⁵ and Hiroshi Kobayashi¹

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AAV expression of a blood-brain barrier-penetrating form of β-galactosidase normalises GM1 ganglioside storage in mice

Saki Kondo Matsushima,1 Yohta Shimada,1 Masafumi Kinoshita,2 Takashi Nagashima,3 Shinichiro Okamoto,4 Sayoko Iizuka,1 Haruna Takagi,2 Shunsuke Iizuka,2 Takashi Higuchi,1 Hiroyuki Hioki,4 Ayako M. Watabe,3 Hiroyuki Sonoda,2 Toya Ohashi,5 and Hiroshi Kobayashi1

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Saki Kondo Matsushima,¹ Yohta Shimada,¹ Masafumi Kinoshita,² Takashi Nagashima,³ Shinichiro Okamoto,⁴ Sayoko Iizuka,¹ Haruna Takagi,² Shunsuke Iizuka,² Takashi Higuchi,¹ Hiroyuki Hioki,⁴ Ayako M. Watabe,³ Hiroyuki Sonoda,² Toya Ohashi,⁵ and Hiroshi Kobayashi¹