University of Pittsburgh researchers have developed an experimental mRNA therapy that dramatically extends the treatment window for acetaminophen overdose in preclinical mouse models. By delivering mRNA coding for the protective protein SRXN1 via lipid nanoparticles, the therapy remained effective six hours after an overdose, whereas the standard antidote, N-acetylcysteine, loses efficacy after two hours. The therapy leverages a newly discovered SRXN1-USP7-HO-1 pathway that helps liver cells survive intense oxidative stress.
Efficacy of the mRNA therapy in mice
- ▪The experimental mRNA treatment remained effective in mice when administered six hours after an acetaminophen overdose.
- ▪University of Pittsburgh researchers developed an experimental mRNA therapy that reduced liver injury in mice following an acetaminophen overdose.
Design and delivery of the mRNA therapy
- ▪The experimental mRNA therapy delivers mRNA coding for SRXN1, a protective protein known to help cells reverse oxidative damage.
- ▪Senior author Wen Xie noted that mRNA acts very quickly, making it highly suitable for treating acute events like an acetaminophen overdose.
- ▪Researchers packaged the SRXN1 mRNA using lipid nanoparticles, the same delivery technology utilized in mRNA COVID-19 vaccines.
The role of SRXN1 in liver protection
- ▪Genetically engineered mice lacking the SRXN1 protein experienced significantly more severe liver injury from overdose, while mice with elevated SRXN1 levels were protected.
- ▪Researchers identified a previously unrecognized liver-protection pathway where the protein SRXN1 protects the protein USP7, which in turn stabilizes the antioxidant-defense molecule HO-1.
- ▪Analysis of liver samples from patients who died of acetaminophen overdose revealed that SRXN1 levels increased during the injury process.
Limitations of the current antidote
- ▪The only FDA-approved antidote for acetaminophen overdose-related liver injury is N-acetylcysteine, which must be administered within hours to be effective.
- ▪The currently approved antidote, N-acetylcysteine, provides complete protection at one hour and partial protection at two hours in mice, but no protection beyond that point.
Dangers of acetaminophen
- ▪Acetaminophen overdose is a very common cause of emergency room visits for liver failure and represents a serious clinical problem.
- ▪Acetaminophen becomes dangerous when misused, such as when people accidentally take multiple over-the-counter medications containing the drug.
Debatable claims
- ▪mRNA technology is the most promising pathway to address acute drug overdoses
- ▪Developing novel mRNA therapies is a better use of funding than improving existing antidotes
- ▪Preclinical success in mice justifies rapid human testing of SRXN1 mRNA therapy
- ▪Lipid nanoparticles are safe enough for use in acute liver therapies
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