Targeting AASS alleviates neurotoxicity and improves mitochondrial function in astrocyte models for pyridoxine-dependent epilepsy

Imke M. E. Schuurmans; Udo Engelke; Muna Abedrabbo; Sofía Puvogel; Rachel Mijdam; Gijs-Jan Scholten; Sara B. van Katwijk; Astrid Oudakker; Hilal H. Al-Shekaili; Dirk J. Lefeber; Blair R. Leavitt; Clara D. M. van Karnebeek; Nael Nadif Kasri; Alejandro Garanto

doi:10.1016/j.omtn.2025.102728

Targeting AASS alleviates neurotoxicity and improves mitochondrial function in astrocyte models for pyridoxine-dependent epilepsy

Imke M. E. Schuurmans
, Udo Engelke
, Muna Abedrabbo
, Sofía Puvogel
, Rachel Mijdam
, Gijs-Jan Scholten
, Sara B. van Katwijk
, Astrid Oudakker
, Hilal H. Al-Shekaili
, Dirk J. Lefeber
, Blair R. Leavitt
, Clara D. M. van Karnebeek
, Nael Nadif Kasri
, Alejandro Garanto^*

^*Corresponding author for this work

Radboud University Nijmegen
Amsterdam UMC - University of Amsterdam
Changing Rare Disorders of Lysine Metabolism (CHARLIE) International Consortium
University of British Columbia
Sultan Qaboos University
United for Metabolic Diseases

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Using patient-derived astrocytes, Schuurmans and colleagues show that pyridoxine-dependent epilepsy (PDE) causes toxic metabolite buildup, oxidative stress, and mitochondrial dysfunction. These phenotypes were (partially) rescued by downregulating AASS upstream in the lysine pathway, providing first proof of concept for a translatable therapy for patients with PDE and highlighting potential for other neurometabolic disorders.

Original language	English
Article number	102728
Journal	Molecular Therapy Nucleic Acids
Volume	36
Issue number	4
DOIs	https://doi.org/10.1016/j.omtn.2025.102728
Publication status	Published - 9 Dec 2025

Keywords

AASS
ALDH7A1
MT: Oligonucleotides: Therapies and Applications
antisense oligonucleotides
astrocytes
human disease modeling
induced pluripotent stem cells
lysine metabolism disorders
metabolic diseases

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Targeting-aass-alleviates-neurotoxicity-and-improves-mitochondrial-function-in-astrocyte-models-for-pyridoxine-dependent.pdfFinal published version, 14 MBLicence: CC BY

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Schuurmans, I. M. E., Engelke, U., Abedrabbo, M., Puvogel, S., Mijdam, R., Scholten, G.-J., van Katwijk, S. B., Oudakker, A., Al-Shekaili, H. H., Lefeber, D. J., Leavitt, B. R., van Karnebeek, C. D. M., Nadif Kasri, N., & Garanto, A. (2025). Targeting AASS alleviates neurotoxicity and improves mitochondrial function in astrocyte models for pyridoxine-dependent epilepsy. Molecular Therapy Nucleic Acids, 36(4), Article 102728. https://doi.org/10.1016/j.omtn.2025.102728

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title = "Targeting AASS alleviates neurotoxicity and improves mitochondrial function in astrocyte models for pyridoxine-dependent epilepsy",

abstract = "Using patient-derived astrocytes, Schuurmans and colleagues show that pyridoxine-dependent epilepsy (PDE) causes toxic metabolite buildup, oxidative stress, and mitochondrial dysfunction. These phenotypes were (partially) rescued by downregulating AASS upstream in the lysine pathway, providing first proof of concept for a translatable therapy for patients with PDE and highlighting potential for other neurometabolic disorders.",

keywords = "AASS, ALDH7A1, MT: Oligonucleotides: Therapies and Applications, antisense oligonucleotides, astrocytes, human disease modeling, induced pluripotent stem cells, lysine metabolism disorders, metabolic diseases",

author = "Schuurmans, \{Imke M. E.\} and Udo Engelke and Muna Abedrabbo and Sof{\'i}a Puvogel and Rachel Mijdam and Gijs-Jan Scholten and \{van Katwijk\}, \{Sara B.\} and Astrid Oudakker and Al-Shekaili, \{Hilal H.\} and Lefeber, \{Dirk J.\} and Leavitt, \{Blair R.\} and \{van Karnebeek\}, \{Clara D. M.\} and \{Nadif Kasri\}, Nael and Alejandro Garanto",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors.",

year = "2025",

month = dec,

day = "9",

doi = "10.1016/j.omtn.2025.102728",

language = "English",

volume = "36",

journal = "Molecular Therapy Nucleic Acids",

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Schuurmans, IME, Engelke, U, Abedrabbo, M, Puvogel, S, Mijdam, R, Scholten, G-J, van Katwijk, SB, Oudakker, A, Al-Shekaili, HH, Lefeber, DJ, Leavitt, BR, van Karnebeek, CDM, Nadif Kasri, N & Garanto, A 2025, 'Targeting AASS alleviates neurotoxicity and improves mitochondrial function in astrocyte models for pyridoxine-dependent epilepsy', Molecular Therapy Nucleic Acids, vol. 36, no. 4, 102728. https://doi.org/10.1016/j.omtn.2025.102728

TY - JOUR

T1 - Targeting AASS alleviates neurotoxicity and improves mitochondrial function in astrocyte models for pyridoxine-dependent epilepsy

AU - Schuurmans, Imke M. E.

AU - Engelke, Udo

AU - Abedrabbo, Muna

AU - Puvogel, Sofía

AU - Mijdam, Rachel

AU - Scholten, Gijs-Jan

AU - van Katwijk, Sara B.

AU - Oudakker, Astrid

AU - Al-Shekaili, Hilal H.

AU - Lefeber, Dirk J.

AU - Leavitt, Blair R.

AU - van Karnebeek, Clara D. M.

AU - Nadif Kasri, Nael

AU - Garanto, Alejandro

PY - 2025/12/9

Y1 - 2025/12/9

N2 - Using patient-derived astrocytes, Schuurmans and colleagues show that pyridoxine-dependent epilepsy (PDE) causes toxic metabolite buildup, oxidative stress, and mitochondrial dysfunction. These phenotypes were (partially) rescued by downregulating AASS upstream in the lysine pathway, providing first proof of concept for a translatable therapy for patients with PDE and highlighting potential for other neurometabolic disorders.

AB - Using patient-derived astrocytes, Schuurmans and colleagues show that pyridoxine-dependent epilepsy (PDE) causes toxic metabolite buildup, oxidative stress, and mitochondrial dysfunction. These phenotypes were (partially) rescued by downregulating AASS upstream in the lysine pathway, providing first proof of concept for a translatable therapy for patients with PDE and highlighting potential for other neurometabolic disorders.

KW - AASS

KW - ALDH7A1

KW - MT: Oligonucleotides: Therapies and Applications

KW - antisense oligonucleotides

KW - astrocytes

KW - human disease modeling

KW - induced pluripotent stem cells

KW - lysine metabolism disorders

KW - metabolic diseases

UR - https://www.scopus.com/pages/publications/105021211445

U2 - 10.1016/j.omtn.2025.102728

DO - 10.1016/j.omtn.2025.102728

M3 - Article

C2 - 41158987

SN - 2162-2531

VL - 36

JO - Molecular Therapy Nucleic Acids

JF - Molecular Therapy Nucleic Acids

IS - 4

M1 - 102728

ER -

Targeting AASS alleviates neurotoxicity and improves mitochondrial function in astrocyte models for pyridoxine-dependent epilepsy

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