mRNA-LNP therapy restores systemic nucleoside imbalance in a mitochondrial DNA depletion syndrome
Year: 2026
Type: preprint
Abstract: Mitochondrial DNA depletion syndromes (MDS) are inherited conditions caused by pathogenic variants in mitochondrial DNA maintenance genes. Most MDS are severe, fatal and incurable conditions. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an MDS resulting from loss-of-function mutations in the TYMP gene, encoding Thymidine Phosphorylase (TP). Systemic nucleoside accumulation caused by TP deficiency disrupts mitochondrial nucleotide homeostasis, which underlies disease progression and mortality. Current treatments, including liver and hematopoietic stem cell transplantation, partially restore TP activity but are invasive, carry substantial risk and are limited by donor availability. Here, we establish TYMP -mRNA in lipid nanoparticles ( hTYMP -mRNA-LNPs) as a safe non-viral protein-replacement therapy for MNGIE. Intravenous administration of hTYMP -mRNA-LNPs induced robust hepatic TP expression in a mouse model of MNGIE, was well tolerated and restored circulating nucleosides to wild-type levels within hours, lasting up to three weeks, at a preclinical minimally effective dose of 0.25mg/kg. To facilitate repeat administration and patient access, we demonstrate enhanced efficiency of subcutaneous mRNA-LNP delivery by co-administration of recombinant or mRNA-encoded ( SPAM1 -mRNA-LNPs) hyaluronidase, achieving effective hepatic TP expression and systemic nucleoside clearance. These findings establish mRNA-LNP-mediated protein replacement as a therapeutic strategy for a primary mitochondrial disease where transient liver-targeted expression is sufficient to correct a systemic metabolic defect. More broadly, our results support the development of mRNA-LNP therapeutics and their subcutaneous delivery as a generalizable platform for treating monogenic diseases, through repeatable, non-viral protein replacement.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: United Mitochondrial Disease Foundation, Muscular Dystrophy UK, LifeArc, UK Research and Innovation, Australian Government, Rosetrees Trust, University of Queensland, Therapeutic Innovation Australia, Medical Research Council, Biotechnology and Biological Sciences Research Council, Australian Research Council, Instituto de Salud Carlos III, European Regional Development Fund
Awards: G1131702584, Nuevos modelos in vitro e in vivo para estudiar terapias en trastornos del mantenimiento del DNA mitocondrial, G2208523090, G2228563315, MitoCluster: an integrated phenotyping and mouse model generation platform for mitochondrial disease and dysfunction, Mitochondria in development: Neural stem cell-niche interactions that protect the developing and aging brain against mitochondrial dysfunction, G5057675360, Preventing dedifferentiation of neurons: a role for H3K9me- and HP1 associated heterochromatin?, G5549861300, G7150264529, G7327507430, G7798797775, G7840255920, G799129384, G864407001
OpenAlex ID: W7211970624