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Systemic delivery of AAV-GFM1 corrects COXPD1 molecular alterations in Gfm1<sup>R671C/-</sup> mice.

Overview

Authors: Miguel Molina-Berenguer1,2, Diego Herrero-Martínez3, Antoni Vallbona-Garcia1, Ferran Vila-Julià1, Yolanda Cámara1, África Vales3, Gloria González-Aseguinolaza3, Javier Torres-Torronteras1,4,5, Ramon Martí1
ORCID iDs: Miguel Molina-Berenguer, Diego Herrero-Martínez, Antoni Vallbona-Garcia, Ferran Vila-Julià, Yolanda Cámara, África Vales, Gloria González-Aseguinolaza, Javier Torres-Torronteras, Ramon Martí
  1. Research Group on Neuromuscular and Mitochondrial Diseases, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, and Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III,Barcelona, Spain
  2. Institute for Bioengineering of Catalonia (IBEC),Barcelona, Spain
  3. Programa de Investigación de Terapia Génica de Enfermedades Raras, División de Medicina de ADN y ARN, Centro de Investigación Médica Aplicada (CIMA),Pamplona, Spain
  4. Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation,Barcelona, Spain
  5. Hospital del Mar Research Institute,Barcelona, Spain
Institutions: Instituto de Salud Carlos III (Spain); Institute for Bioengineering of Catalonia (Spain); Centro de Investigación Médica Aplicada (Spain); Barcelonaβeta Brain Research Center (Spain); Hospital del Mar Research Institute (Spain)
Journal: EMBO molecular medicine, volume 18, issue 6, pages 2152-2179
Dates: received 3 October 2025; accepted 1 April 2026; published online 17 April 2026; in print June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s44321-026-00426-4 · PMID 41998139 · PMCID PMC13269562 · OpenAlex W7154712395
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: human (organism), mouse (organism), cellular / molecular (subfield)
Methods: Statistics
Keywords: Genetics, Gene Therapy & Genetic Disease
MeSH: Dependovirus*, Genetic Therapy*, Mitochondrial Diseases*, Peptide Elongation Factor 1*, Animals, Brain, Disease Models, Animal, Genetic Vectors, Humans, Liver, Mice, Mice, Knockout, Mitochondria, Oxidative Phosphorylation (* major topic)
Topic: Mitochondrial Function and Pathology (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: Fundación Mutua Madrileña (Mutua Madrileña Foundation) (AP176532021); Fundacion Mencia (DRUG4_COXPD1); Ministerio de Ciencia e Innovación (PRTR-C17.I1); Generalitat de Catalunya (DRUG4_COXPD1); Fundacion Adey (COXPD1); Dona Pilar Millan-Cromomed (Fellowship 01)
Citations: not cited yet (Europe PMC); 74 references in the paper

Abstract

Hepatoencephalopathy due to mutations in the nuclear gene GFM1, known as combined oxidative phosphorylation (OXPHOS) deficiency type I (COXPD1), is an autosomal recessive mitochondrial disease caused by defects or deficiency of the mitochondrial translation elongation factor G1 (EFG1), with no currently available cure. Patients with COXPD1 develop a severe encephalopathy, sometimes combined with liver failure, with neonatal onset and rapid progression that normally causes premature death. The Gfm1R671C/− mouse recapitulates the COXPD1 molecular phenotype in liver and brain, with drastic reduction of EFG1 levels, impaired mitochondrial translation, and OXPHOS deficiency. We conducted a gene therapy study using two different recombinant adeno-associated virus (rAAV) vectors targeting the liver or the brain to introduce the human GFM1 gene into 6-week-old Gfm1R671C/− mice. Successful transduction of the liver and the brain was observed after four weeks, entailing substantial recovery from mitochondrial EFG1 depletion and OXPHOS correction in both tissues, which demonstrates that transgenic human EFG1 is functional in mouse mitochondrial translation. Our study constitutes the first evidence supporting AAV-mediated gene therapy as a potential treatment for COXPD1.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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Data availability

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The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44321-026-00426-4 (https://www.ebi.ac.uk/biostudies/sourcedata/studies/S-SCDT-10_1038-S44321-026-00426-4).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 9 authors, 1 keyword, 14 MeSH terms, 6 funders, 74 references.

Cite

This paper

Molina-Berenguer, M., Herrero-Martínez, D., Vallbona-Garcia, A., Vila-Julià, F., Cámara, Y., Vales, Á., González-Aseguinolaza, G., Torres-Torronteras, J., & Martí, R. (2026). Systemic delivery of AAV-GFM1 corrects COXPD1 molecular alterations in Gfm1<sup>R671C/-</sup> mice. EMBO molecular medicine, 18(6), 2152-2179. https://doi.org/10.1038/s44321-026-00426-4

BibTeX

@article{molinaberenguer2026systemic,
author = {Molina-Berenguer, Miguel and Herrero-Martínez, Diego and Vallbona-Garcia, Antoni and Vila-Julià, Ferran and Cámara, Yolanda and Vales, África and González-Aseguinolaza, Gloria and Torres-Torronteras, Javier and Martí, Ramon},
title = {{Systemic delivery of AAV-GFM1 corrects COXPD1 molecular alterations in Gfm1\<sup\>R671C/-\</sup\> mice}},
journal = {EMBO molecular medicine},
year = {2026},
month = apr,
volume = {18},
number = {6},
pages = {2152--2179},
publisher = {Nature Publishing Group},
issn = {1757-4676},
doi = {10.1038/s44321-026-00426-4},
url = {https://doi.org/10.1038/s44321-026-00426-4},
pmid = {41998139},
pmcid = {PMC13269562}
}

RIS

TY - JOUR
AU - Molina-Berenguer, Miguel
AU - Herrero-Martínez, Diego
AU - Vallbona-Garcia, Antoni
AU - Vila-Julià, Ferran
AU - Cámara, Yolanda
AU - Vales, África
AU - González-Aseguinolaza, Gloria
AU - Torres-Torronteras, Javier
AU - Martí, Ramon
TI - Systemic delivery of AAV-GFM1 corrects COXPD1 molecular alterations in Gfm1<sup>R671C/-</sup> mice
T2 - EMBO molecular medicine
J2 - EMBO Mol Med
PY - 2026
DA - 2026/04/17
VL - 18
IS - 6
SP - 2152
EP - 2179
SN - 1757-4676
PB - Nature Publishing Group
DO - 10.1038/s44321-026-00426-4
UR - https://doi.org/10.1038/s44321-026-00426-4
LA - en
ER -

CSL-JSON

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