Gene therapy prevents hepatic mitochondrial dysfunction in murine deoxyguanosine kinase deficiency
Primary mitochondrial disorders are a cause of neonatal liver failure. Biallelic pathogenic variants of the gene encoding the mitochondrial localizing enzyme deoxyguanosine kinase (DGUOK) cause hepatocerebral mitochondrial DNA depletion syndrome, leading to acute neonatal liver failure and early mortality. There are currently no effective disease-modifying therapies. In this study, we developed an adeno-associated virus 9 (AAV9) gene therapy approach to treat a mouse model of DGUOK deficiency that recapitulates human disease. We delivered AAV9-<i>hDGUOK</i> intravenously to newborn <i>Dguok</i> knock-out mice and showed that liver dysfunction was prevented in a dose-dependent manner. Unexpectedly for neonatal delivery, durable and long-lasting liver transduction and RNA expression were observed. Liver mitochondrial DNA depletion, deficiencies of oxidative phosphorylation complexes I, III, and IV and liver transaminitis and survival were ameliorated in a dose-dependent manner.
Authors
- John R. Counsell (ORCID: https://orcid.org/0000-0001-9208-101X)
- Simon N. Waddington (ORCID: https://orcid.org/0000-0003-4970-4730)
- Anna Karlsson (ORCID: https://orcid.org/0000-0001-6843-6685)
- Neil J. Sebire (ORCID: https://orcid.org/0000-0001-5348-9063)
- Helen Prunty (ORCID: https://orcid.org/0000-0002-8889-2423)
- Juan Antinao Díaz (ORCID: https://orcid.org/0000-0001-7295-2738)
- Shamima Rahman (ORCID: https://orcid.org/0000-0003-2088-730X)
- Rajvinder Karda (ORCID: https://orcid.org/0000-0001-9821-483X)
- Nandaki Keshavan (ORCID: https://orcid.org/0000-0001-6939-4528)
- Riccardo Privolizzi (ORCID: https://orcid.org/0000-0001-5699-9587)
- Miriam Greenwood (ORCID: https://orcid.org/0009-0004-3262-2979)
Institutions
- Karolinska University Hospital (SE)
- Great Ormond Street Hospital (GB)
- Karolinska Institutet (SE)
- Institute of Child Health (GR)
- Institute for Reproductive Health (US)
- University College London (GB)
Publication Details
- Journal
- Molecular Therapy — Methods & Clinical Development
- Published
- 2024-12-13
- DOI
- https://doi.org/10.1016/j.omtm.2024.101397
- Citations
- 3
- Primary Topic
- Metabolism and Genetic Disorders
- Type
- article
- Field-Weighted Citation Impact
- 1.14
Funders
- LifeArc
- Action Medical Research
- National Institute for Health and Care Research
- Wellbeing of Women
- Great Ormond Street Hospital Charity
- Cancerfonden
- Great Ormond Street Hospital for Children
- Karolinska Institutet
- Vetenskapsrådet
- Lily Foundation
- Medical Research Council
- NIHR Great Ormond Street Hospital Biomedical Research Centre