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Peer-reviewedCC BYMolecular therapy. Advances

AAV vector-mediated ALDH5A1 gene replacement improves survival and metabolic correction in a severe mouse model of SSADH deficiency

  • Kiri Koshu1
  • Ayumi Horiguchi1
  • Teru Mizuno1
  • Shiho Aoki1
  • Miyuki Watanabe1
  • Naomi Takino2
  • Mika Ito2
  • Eriko F. Jimbo1
  • Kazuhiro Muramatsu1
  • Shin-Ichi Muramatsu2
  • Hitoshi Osaka1
  1. 1Department of Pediatrics, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan
  2. 2Division of Neurological Gene Therapy, Center for Open Innovation, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan
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Abstract

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a severe neurometabolic disorder characterized by γ-aminobutyric acid (GABA) and γ-hydroxybutyrate (GHB) accumulation, causing network hyperexcitability, progressive neuroglial pathology, and premature death. Currently, no curative therapy is available. We developed an adeno-associated virus (AAV) vector expressing human aldehyde dehydrogenase 5 family member A1 and assessed its therapeutic efficacy in a severe SSADH-deficient mouse model following neonatal administration at escalating doses. AAV vector-mediated gene replacement conferred therapeutic benefit, including extended survival, reduced mortality, enhanced motor performance, and significant reductions in urinary GABA and GHB levels. The survival benefit was most evident at the high dose, suggesting the presence of an apparent therapeutic threshold for survival benefit. Vector genomes were distributed throughout the central nervous system and liver, with the robust restoration of SSADH expression in the central nervous system. These findings provide strong preclinical justification for the clinical translation of central nervous system-directed AAV vector gene therapy in this disorder.

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Cite

BibTeXRIS
BibTeX
@article{koshu2026vectormediated,
  title = {{AAV vector-mediated ALDH5A1 gene replacement improves survival and metabolic correction in a severe mouse model of SSADH deficiency}},
  author = {Kiri Koshu and Ayumi Horiguchi and Teru Mizuno and Shiho Aoki and Miyuki Watanabe and Naomi Takino and Mika Ito and Eriko F. Jimbo and Kazuhiro Muramatsu and Shin-Ichi Muramatsu and Hitoshi Osaka},
  journal = {Molecular therapy. Advances},
  year = {2026},
  month = oct,
  doi = {10.1016/j.omta.2026.201860},
  url = {https://europepmc.org/article/PMC/PMC13718803},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - AAV vector-mediated ALDH5A1 gene replacement improves survival and metabolic correction in a severe mouse model of SSADH deficiency
AU  - Kiri Koshu
AU  - Ayumi Horiguchi
AU  - Teru Mizuno
AU  - Shiho Aoki
AU  - Miyuki Watanabe
AU  - Naomi Takino
AU  - Mika Ito
AU  - Eriko F. Jimbo
AU  - Kazuhiro Muramatsu
AU  - Shin-Ichi Muramatsu
AU  - Hitoshi Osaka
PY  - 2026
DA  - 2026/10/07
JO  - Molecular therapy. Advances
DO  - 10.1016/j.omta.2026.201860
UR  - https://europepmc.org/article/PMC/PMC13718803
AB  - Succinic semialdehyde dehydrogenase (SSADH) deficiency is a severe neurometabolic disorder characterized by γ-aminobutyric acid (GABA) and γ-hydroxybutyrate (GHB) accumulation, causing network hyperexcitability, progressive neuroglial pathology, and premature death. Currently, no curative therapy is available. We developed an adeno-associated virus (AAV) vector expressing human aldehyde dehydrogenase 5 family member A1 and assessed its therapeutic efficacy in a severe SSADH-deficient mouse model following neonatal administration at escalating doses. AAV vector-mediated gene replacement conferred therapeutic benefit, including extended survival, reduced mortality, enhanced motor performance, and significant reductions in urinary GABA and GHB levels. The survival benefit was most evident at the high dose, suggesting the presence of an apparent therapeutic threshold for survival benefit. Vector genomes were distributed throughout the central nervous system and liver, with the robust restoration of SSADH expression in the central nervous system. These findings provide strong preclinical justification for the clinical translation of central nervous system-directed AAV vector gene therapy in this disorder.
SN  - 3117-387X
ER  -