mRNA-LNP therapy restores systemic nucleoside imbalance in a mitochon-drial DNA depletion syndrome

Mitochondrial DNA depletion syndromes (MDS) are rare, inherited disorders caused by mutations in genes responsible for maintaining mitochondrial DNA. The most severe form, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), arises from loss-of-function mutations in the TYMP gene, which provides instructions for making Thymidine Phosphorylase (TP).

TP deficiency leads to an imbalance of nucleosides in the body, disrupting essential mitochondrial functions and ultimately causing disease progression and death. Currently, treatments like liver and stem cell transplants can partially restore TP activity, but they are risky, invasive, and limited by donor availability.

In a recent study, researchers demonstrated that delivering TYMP mRNA within lipid nanoparticles (hTYMP-mRNA-LNPs) can safely and effectively replace the missing TP protein in a mouse model of MNGIE. When administered intravenously, hTYMP-mRNA-LNPs stimulated the liver to produce sufficient TP, restoring the body's nucleoside balance within hours and maintaining this balance for up to three weeks at a dose of just 0.25mg/kg.

To improve treatment accessibility, the team also showed that co-administering the mRNA-LNP with recombinant or mRNA-encoded hyaluronidase (SPAM1-mRNA-LNPs) enhances the delivery of the therapy to the liver. This combination led to effective TP expression and clearance of excess nucleosides from the bloodstream, further extending the duration of the therapeutic effect.

These findings highlight the potential of mRNA-LNP technology as a safe, non-viral approach to protein replacement therapy for primary mitochondrial diseases like MNGIE. By targeting and restoring the function of the TP enzyme in the liver, this treatment could potentially correct systemic metabolic defects without the need for invasive procedures.

Moreover, the researchers' success in delivering mRNA-LNPs subcutaneously opens the door to a more broadly applicable platform for treating a variety of monogenic disorders through repeatable, non-viral protein replacement strategies.