Research ArticleMetabolismTherapeutics Open Access | 10.1172/JCI163464

Kentaro Ito,1,2 Go Tajima,2,3 Chikako Kamisato,1 Miyuki Tsumura,2 Mitsuhiro Iwamoto,4 Yukiko Sekiguchi,4 Yukinobu Numata,4 Kyoko Watanabe,5 Yoshiyuki Yabe,5 Satomi Kanki,5 Yusuke Fujieda,6 Koichi Goto,7 Yoshitaka Sogawa,6 Masataka Oitate,5 Hiroyuki Nagase,1 Shinnosuke Tsuji,1 Tomohiro Nishizawa,1 Masayo Kakuta,1 Takeshi Masuda,4 Yoshiyuki Onishi,4 Makoto Koizumi,4 Hidefumi Nakamura,8 Satoshi Okada,2 Masafumi Matsuo,9 and Kiyosumi Takaishi1

1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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

1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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

1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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

1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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

1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

Find articles by Watanabe, K. in: JCI | PubMed | Google Scholar

1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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

1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

Find articles by Goto, K. in: JCI | PubMed | Google Scholar

1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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

1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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

1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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

1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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

1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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

1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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

1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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

1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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

1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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

1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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

1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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

1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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

1Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

2Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

3Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, Tokyo, Japan.

4Modality Research Laboratories,

5Drug Metabolism and Pharmacokinetics Research Laboratories,

6Translational Science Department II, and

7Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

8Department of Research and Development Supervision, National Center for Child Health and Development, Tokyo, Japan.

9Research Center for Locomotion Biology, Kobe Gakuin University, Kobe, Japan.

Address correspondence to: Kiyosumi Takaishi, Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd; Shinagawa-ku, Tokyo, 140-8710, Japan. Phone: 81.3.34923131; Email: takaishi.kiyosumi.nj@daiichisankyo.co.jp.

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Published October 3, 2023 - More info

Published in Volume 133, Issue 23 on December 1, 2023
J Clin Invest. 2023;133(23):e163464. https://doi.org/10.1172/JCI163464.
© 2023 Ito 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 October 3, 2023 - Version history
Received: July 26, 2022; Accepted: September 27, 2023 View PDF Abstract

Glycogen storage disease type 1a (GSD1a) is caused by a congenital deficiency of glucose-6-phosphatase-α (G6Pase-α, encoded by G6PC), which is primarily associated with life-threatening hypoglycemia. Although strict dietary management substantially improves life expectancy, patients still experience intermittent hypoglycemia and develop hepatic complications. Emerging therapies utilizing new modalities such as adeno-associated virus and mRNA with lipid nanoparticles are under development for GSD1a but potentially require complicated glycemic management throughout life. Here, we present an oligonucleotide-based therapy to produce intact G6Pase-α from a pathogenic human variant, G6PC c.648G>T, the most prevalent variant in East Asia causing aberrant splicing of G6PC. DS-4108b, a splice-switching oligonucleotide, was designed to correct this aberrant splicing, especially in liver. We generated a mouse strain with homozygous knockin of this variant that well reflected the pathophysiology of patients with GSD1a. DS-4108b recovered hepatic G6Pase activity through splicing correction and prevented hypoglycemia and various hepatic abnormalities in the mice. Moreover, DS-4108b had long-lasting efficacy of more than 12 weeks in mice that received a single dose and had favorable pharmacokinetics and tolerability in mice and monkeys. These findings together indicate that this oligonucleotide-based therapy could provide a sustainable and curative therapeutic option under easy disease management for GSD1a patients with G6PC c.648G>T.

Graphical Abstract Introduction

Glycogen storage diseases are rare genetic disorders characterized by the dysfunction of enzymes involved in glycogen metabolism (1). Glycogen storage disease type 1a (GSD1a, OMIM: 232200) is an autosomal recessively inherited inborn error of metabolism defined by impairment of glucose-6-phosphatase-α (G6Pase-α, encoded by the G6PC gene) with a prevalence of approximately 1 in 100,000 individuals (2–4). G6Pase-α is the enzyme involved in the hydrolysis of glucose-6-phosphate (G6P) and the production of glucose as the last step of glycogenolysis and gluconeogenesis and is mainly expressed in liver, kidney, and small intestine. Patients with GSD1a manifest severe fasting hypoglycemia due to impaired glucose production and secondary metabolic abnormalities (lactic acidosis, hyperuricemia, hyperlipidemia) associated with excessive G6P production. These metabolic abnormalities lead to the accumulation of glycogen and fat in the liver and kidney, resulting in hepatomegaly and nephromegaly. GSD1a was once a fatal disease in infancy due to severe hypoglycemia, but the life expectancy and prognosis have been substantially improved by introducing frequent (every 4–6 h) intake of a starch-rich diet against life-threatening hypoglycemia as a standard of care. Despite the heavy burden on patients and their families, this approach does not sufficiently prevent biochemical hypoglycemia, glycogen accumulation, or other metabolic abnormalities that lead to hepatocellular adenoma/carcinoma (HCA/HCC) and renal injury (3–8).

The only curative treatment for these patients is liver/kidney transplantation (9), but this is also associated with various difficulties. Thus, curative and less invasive therapies are highly desired. Several gene replacement therapies based on viral vectors have shown promise in correcting hypoglycemia and preventing various complications in GSD1a animal models (10–14), among which an adeno-associated virus–based (AAV-based) product is currently being evaluated in clinical trials (e.g., ClinicalTrials.gov, NCT03517085). However, emerging evidence suggests that AAV therapies may not endure as a lifelong treatment option for patients, and readministration might also be ineffective (15–17). Aside from gene replacement therapies, mRNA replacement therapy based on lipid-nanoparticle technology, which delivers the mRNA to the liver, has also shown beneficial effects on the symptoms in GSD1a model mice (18, 19) and is under evaluation in its first clinical trial (ClinicalTrials.gov, NCT05095727). Although it is likely to be a lifelong treatment option for GSD1a, it may still require complicated dietary management as a result of G6PC promoter–independent G6Pase-α levels not being regulated by glucose homeostasis control and a rapid decline in efficacy with a short half-life of the translated protein (19, 20).

To develop a lifelong and easy-to-manage GSD1a treatment, we evaluated an oligonucleotide-based therapy to produce intact G6Pase-α from a prevalent pathogenic human variant, G6PC c.648G>T. This variant is particularly identified in East Asian patients with GSD1a, accounting for 91%, 75%, and 54% of the alleles in Japanese, Korean, and Chinese patients, respectively (21). This variant causes aberrant splicing, in which 91 nucleotides from the 5′ end of exon 5 are removed, resulting in the loss of G6Pase-α activity (22,