Establishment of mouse model of inherited PIGO deficiency and therapeutic potential of AAV-based gene therapy

Ryoko Kuwayama; Keiichiro Suzuki; Jun Nakamura; Emi Aizawa; Yoshichika Yoshioka; Masahito Ikawa; Shin Nabatame; Ken-Ichi Inoue; Yoshiari Shimmyo; Keiichi Ozono; Taroh Kinoshita; Yoshiko Murakami

doi:10.1038/s41467-022-30847-x

Establishment of mouse model of inherited PIGO deficiency and therapeutic potential of AAV-based gene therapy

Nat Commun. 2022 Jun 3;13(1):3107. doi: 10.1038/s41467-022-30847-x.

Authors

Ryoko Kuwayama^{1

2}, Keiichiro Suzuki^{3

4

5}, Jun Nakamura³, Emi Aizawa⁴, Yoshichika Yoshioka^{3

6

7}, Masahito Ikawa⁸, Shin Nabatame², Ken-Ichi Inoue⁹, Yoshiari Shimmyo¹⁰, Keiichi Ozono², Taroh Kinoshita^{1

11}, Yoshiko Murakami¹²

Affiliations

¹ Yabumoto Department of Intractable disease research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
² Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.
³ Graduate School of Frontier Bioscience, Osaka University, Osaka, Japan.
⁴ Graduate School of Engineering Science, Osaka University, Osaka, Japan.
⁵ Institute for Advanced Co-Creation Studies, Osaka University, Osaka, Japan.
⁶ Center for Information and Neural Networks, National Institute of Information and Communications Technology (NICT) and Osaka University, Osaka, Japan.
⁷ Center for Quantum Information and Quantum Biology, Osaka University, Osaka, Japan.
⁸ Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
⁹ Systems Neuroscience Section, Department of Neuroscience, Primate Research Institute, Kyoto University, Kyoto, Japan.
¹⁰ Asubio Pharma Co., Ltd, Kobe, Japan.
¹¹ Immunoglycobiology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
¹² Yabumoto Department of Intractable disease research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. yoshiko@biken.osaka-u.ac.jp.

Abstract

Inherited glycosylphosphatidylinositol (GPI) deficiency (IGD) is caused by mutations in GPI biosynthesis genes. The mechanisms of its systemic, especially neurological, symptoms are not clarified and fundamental therapy has not been established. Here, we report establishment of mouse models of IGD caused by PIGO mutations as well as development of effective gene therapy. As the clinical manifestations of IGD are systemic and lifelong lasting, we treated the mice with adeno-associated virus for homology-independent knock-in as well as extra-chromosomal expression of Pigo cDNA. Significant amelioration of neuronal phenotypes and growth defect was achieved, opening a new avenue for curing IGDs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Models, Animal
Genetic Therapy
Glycosylphosphatidylinositols* / deficiency
Glycosylphosphatidylinositols* / genetics
Immunoglobulin D / genetics
Mice
Seizures* / genetics

Substances

Glycosylphosphatidylinositols
Immunoglobulin D

Supplementary concepts

Glycosylphosphatidylinositol deficiency