학술논문
A splice-switching oligonucleotide treatment ameliorates glycogen storage disease type 1a in mice with G6PC c.648G>T
Document Type
Academic Journal
Author
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
Source
Journal of Clinical Investigation. December, 2023, Vol. 133 Issue 23
Subject
Language
English
ISSN
0021-9738
Abstract
Glycogen storage disease type 1a (GSD1a) is caused by a congenital deficiency of glucose-6-phosphatase-[alpha] (G6Pase-[alpha], 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-[alpha] 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.
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 [...]
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 [...]