A splice-switching oligonucleotide treatment ameliorates glycogen storage disease type 1a in mice with G6PC c.648G>T
Kentaro Ito, … , Masafumi Matsuo, Kiyosumi Takaishi
Kentaro Ito, … , Masafumi Matsuo, Kiyosumi Takaishi
Published October 3, 2023
Citation Information: J Clin Invest. 2023;133(23):e163464. https://doi.org/10.1172/JCI163464.
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A splice-switching oligonucleotide treatment ameliorates glycogen storage disease type 1a in mice with G6PC c.648G>T

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.

Authors

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

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Figure 5

Metabolomics analysis of liver, kidney, and plasma from cKI-Mut mice given multiple doses of DS-4108b.

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Metabolomics analysis of liver, kidney, and plasma from cKI-Mut mice giv...
(A) The first and second principal components (PC1 and PC2, respectively) of liver, kidney, and plasma in the PCA. Plots from the same individual are presented as the same shape with the same color. Shapes filled with light gray, dark gray, or blue represent groups of vehicle-treated cKI-WT mice, vehicle-treated cKI-Mut mice, and cKI-Mut mice treated with DS-4108b at 10 mg/kg, respectively. (B) Metabolic flux changes of key hepatic metabolites for glycogen metabolism, the EMP pathway, and the pentose phosphate pathway. Quantification results are presented as the mean (nmol/g liver) ± SEM (n = 3). The vehicle-treated cKI-Mut mouse group was compared with the vehicle-treated cKI-WT mouse group using an unpaired, 2-tailed t test. *P < 0.05, **P < 0.01, and ***P < 0.001. DS-4108b–treated cKI-Mut mouse groups were compared with vehicle-treated cKI-Mut mouse group using an unpaired, 2-tailed t test. †P < 0.05 and ††P < 0.01. The abbreviations for each metabolite are defined in the Supplemental Methods.