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...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of clinical investigation 2023-12, Vol.133 (23), p.1-14
Main Authors: Ito, Kentaro, Tajima, Go, Kamisato, Chikako, Tsumura, Miyuki, Iwamoto, Mitsuhiro, Sekiguchi, Yukiko, Numata, Yukinobu, Watanabe, Kyoko, Yabe, Yoshiyuki, Kanki, Satomi, Fujieda, Yusuke, Goto, Koichi, Sogawa, Yoshitaka, Oitate, Masataka, Nagase, Hiroyuki, Tsuji, Shinnosuke, Nishizawa, Tomohiro, Kakuta, Masayo, Masuda, Takeshi, Onishi, Yoshiyuki, Koizumi, Makoto, Nakamura, Hidefumi, Okada, Satoshi, Matsuo, Masafumi, Takaishi, Kiyosumi
Format: Article
Language:English
Subjects:
Animals
Biomedical research
Clinical trials
Disease
Glucose
Glucose-6-phosphatase
Glucose-6-Phosphatase - genetics
Glycogen
Glycogen Storage Disease Type I - complications
Glycogen Storage Disease Type I - genetics
Glycogen Storage Disease Type I - therapy
Humans
Hypoglycemia
Hypoglycemia - genetics
Hypoglycemia - prevention & control
Hypotheses
Life expectancy
Life span
Liver
Liver - pathology
Metabolism
Mice
Mice, Knockout
mRNA
Nanoparticles
Oligonucleotides
Oligonucleotides - genetics
Pathophysiology
Pharmacokinetics
Phosphatase
Plasmids
Splicing
Storage diseases
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI163464