A splice-switching oligonucleotide treatment ameliorates glycogen storage disease type 1a in mice with G6PC c.648G>T
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:133 |
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| Enthalten in: |
The Journal of clinical investigation - 133(2023), 23 vom: 01. Dez. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ito, Kentaro [VerfasserIn] |
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| Links: |
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| Themen: |
EC 3.1.3.9 |
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| Anmerkungen: |
Date Completed 04.12.2023 Date Revised 10.12.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1172/JCI163464 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM362818894 |
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| 100 | 1 | |a Ito, Kentaro |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A splice-switching oligonucleotide treatment ameliorates glycogen storage disease type 1a in mice with G6PC c.648G>T |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Gene therapy | |
| 650 | 4 | |a Genetic diseases | |
| 650 | 4 | |a Glucose metabolism | |
| 650 | 4 | |a Metabolism | |
| 650 | 4 | |a Therapeutics | |
| 650 | 7 | |a Oligonucleotides |2 NLM | |
| 650 | 7 | |a Glucose-6-Phosphatase |2 NLM | |
| 650 | 7 | |a EC 3.1.3.9 |2 NLM | |
| 700 | 1 | |a Tajima, Go |e verfasserin |4 aut | |
| 700 | 1 | |a Kamisato, Chikako |e verfasserin |4 aut | |
| 700 | 1 | |a Tsumura, Miyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Iwamoto, Mitsuhiro |e verfasserin |4 aut | |
| 700 | 1 | |a Sekiguchi, Yukiko |e verfasserin |4 aut | |
| 700 | 1 | |a Numata, Yukinobu |e verfasserin |4 aut | |
| 700 | 1 | |a Watanabe, Kyoko |e verfasserin |4 aut | |
| 700 | 1 | |a Yabe, Yoshiyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Kanki, Satomi |e verfasserin |4 aut | |
| 700 | 1 | |a Fujieda, Yusuke |e verfasserin |4 aut | |
| 700 | 1 | |a Goto, Koichi |e verfasserin |4 aut | |
| 700 | 1 | |a Sogawa, Yoshitaka |e verfasserin |4 aut | |
| 700 | 1 | |a Oitate, Masataka |e verfasserin |4 aut | |
| 700 | 1 | |a Nagase, Hiroyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Tsuji, Shinnosuke |e verfasserin |4 aut | |
| 700 | 1 | |a Nishizawa, Tomohiro |e verfasserin |4 aut | |
| 700 | 1 | |a Kakuta, Masayo |e verfasserin |4 aut | |
| 700 | 1 | |a Masuda, Takeshi |e verfasserin |4 aut | |
| 700 | 1 | |a Onishi, Yoshiyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Koizumi, Makoto |e verfasserin |4 aut | |
| 700 | 1 | |a Nakamura, Hidefumi |e verfasserin |4 aut | |
| 700 | 1 | |a Okada, Satoshi |e verfasserin |4 aut | |
| 700 | 1 | |a Matsuo, Masafumi |e verfasserin |4 aut | |
| 700 | 1 | |a Takaishi, Kiyosumi |e verfasserin |4 aut | |
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