mRNA-LNP therapy restores systemic nucleoside imbalance in a mitochon-drial DNA depletion syndrome
- 1University of Cambridge
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.
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BibTeX
@misc{carrodus2026mrnalnp,
title = {{mRNA-LNP therapy restores systemic nucleoside imbalance in a mitochon-drial DNA depletion syndrome}},
author = {N. L. Carrodus and J. J. Yang and J. Ramon and K. Turner and Y. M. Kanse and S. Petridi and Z. Xiao and A. Dhawanjewar and T. E. Leonard and G. Nolan and A. Quaegebeur and R. Marti and S. W. Cheetham and J. van den Ameele},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.08.750057},
url = {https://www.biorxiv.org/content/10.64898/2026.09.08.750057v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - mRNA-LNP therapy restores systemic nucleoside imbalance in a mitochon-drial DNA depletion syndrome
AU - N. L. Carrodus
AU - J. J. Yang
AU - J. Ramon
AU - K. Turner
AU - Y. M. Kanse
AU - S. Petridi
AU - Z. Xiao
AU - A. Dhawanjewar
AU - T. E. Leonard
AU - G. Nolan
AU - A. Quaegebeur
AU - R. Marti
AU - S. W. Cheetham
AU - J. van den Ameele
PY - 2026
DA - 2026/09/08
PB - bioRxiv
DO - 10.64898/2026.09.08.750057
UR - https://www.biorxiv.org/content/10.64898/2026.09.08.750057v1
AB - 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.
ER -