AAV-based gene therapy ameliorated CNS-specific GPI defect in mouse models

Yoshiko Murakami; Saori Umeshita; Kae Imanishi; Yoshichika Yoshioka; Akinori Ninomiya; Takehiko Sunabori; Shibi Likhite; Masato Koike; Kathrin C Meyer; Taroh Kinoshita

doi:10.1016/j.omtm.2023.101176

AAV-based gene therapy ameliorated CNS-specific GPI defect in mouse models

Mol Ther Methods Clin Dev. 2023 Dec 14;32(1):101176. doi: 10.1016/j.omtm.2023.101176. eCollection 2024 Mar 14.

Authors

Yoshiko Murakami¹, Saori Umeshita¹, Kae Imanishi¹, Yoshichika Yoshioka^{2

3

4}, Akinori Ninomiya⁵, Takehiko Sunabori⁶, Shibi Likhite⁷, Masato Koike⁶, Kathrin C Meyer^{7

8}, Taroh Kinoshita^{1

9}

Affiliations

¹ Laboratory of Immunoglycobiology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
² Graduate School of Frontier Bioscience, Osaka University, Suita, Osaka, Japan.
³ Center for Information and Neural Networks, National Institute of Information and Communications Technology (NICT), Osaka University, Suita, Osaka, Japan.
⁴ Center for Quantum Information and Quantum Biology, Osaka University, Suita, Osaka, Japan.
⁵ Central Instrumentation Laboratory, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
⁶ Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
⁷ Center for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA.
⁸ Department of Pediatrics, The Ohio State University, Columbus, OH, USA.
⁹ Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, Japan.

Abstract

Thirty genes are involved in the biosynthesis and modification of glycosylphosphatidylinositol (GPI)-anchored proteins, and defects in these genes cause inherited GPI deficiency (IGD). PIGA is X-linked and involved in the first step of GPI biosynthesis, and only males are affected by variations in this gene. The main symptoms of IGD are neurological abnormalities, such as developmental delay and seizures. There is no effective treatment at present. We crossed Nestin-Cre mice with Piga-floxed mice to generate CNS-specific Piga knockout (KO) mice. Hemizygous KO male mice died by P10 with severely defective growth. Heterozygous Piga KO female mice are mosaic for Piga expression and showed severe defects in growth and myelination and died by P25. Using these mouse models, we evaluated the effect of gene replacement therapy with adeno-associated virus (AAV). It expressed efficacy within 6 days, and the survival of male mice was extended to up to 3 weeks, whereas 40% of female mice survived for approximately 1 year and the growth defect was improved. However, liver cancer developed in all three treated female mice at 1 year of age, which was probably caused by the AAV vector bearing a strong CAG promoter.

Keywords: GPI-anchored protein; IGD; Pigafloxed; Rian locus; Rtl1; inherited GPI deficiency; nestin-Cre.

Grants and funding

FC001033/ARC_/Arthritis Research UK/United Kingdom