Moderna's First mRNA-Based Protein Replacement Therapy Passes Early Clinical Trials
Moderna, a company known for its successful mRNA COVID-19 vaccine, is now exploring other applications for mRNA technology. These include gene editing therapies, cellular therapies, and replacement therapies.
Moderna's goal since its inception has been to use human cells as drug manufacturing factories. By hijacking the cellular machinery that allows cells to produce therapeutic molecules on their own, Moderna hopes to deliver mRNA to cells for protein replacement therapies.
On May 19, 2023, at the ASGCT Annual Meeting, Moderna reported Phase 1/2 clinical trial data for its mRNA-3927 therapy. This therapy synthesizes propionyl coenzyme A carboxylase by encapsulating two mRNAs encoding two protein subunits, PCCA and PCCB, respectively. These mRNAs are delivered using lipid nanoparticles for the treatment of propionic acidemia (PA).
PA is a rare genetic disorder in which propionic acid and its metabolites accumulate abnormally in the body. This can cause metabolic acidosis, hyperammonemia, brain damage, and multi-organ damage. The disorder is caused by mutations in the PCCA or PCCB genes, which encode a deficiency in propionyl coenzyme A carboxylase activity.
The Phase 1/2 clinical trial showed early signs of efficacy. Prior to mRNA therapy, many patients experienced potentially life-threatening metabolic dysregulation events. After treatment with mRNA-3927 therapy, these patients experienced a significant reduction in the incidence of metabolic dysregulation events. There was a 66% reduction in the overall risk of metabolic dysregulation and a 78% reduction in the risk of metabolic dysregulation in a cohort of four patients who received a single dose of injectable therapy every two weeks. This suggests that mRNA technology can treat propionic acidemia by replacing intracellular proteins.
"As this clinical trial enters the dose escalation phase and we continue to see encouraging results with mRNA-3927, we will continue to evaluate safety and efficacy and determine recommended doses for future clinical trials," said Kyle Holen, M.D., Ph.D., Head of Development, Therapeutics and Oncology at Moderna. "To date, we have treated more than 13 patients for more than one year."
This early success with mRNA-3927 therapy is an exciting development in the field of protein replacement therapies. It demonstrates the potential for mRNA technology to treat genetic disorders by replacing intracellular proteins.
mRNA-based therapeutics have shown great potential in the treatment of various human diseases, particularly malignant tumors. mRNA delivery systems are considered safe and transient methods with a high transduction capacity for disease therapies.
Another example refers to an mRNA-based protein replacement therapy that replaces uridine residues in mRNA with the nucleoside pseudouridine, which has been shown to interrupt innate immune responses caused by RNase and Toll-like receptors. By reducing the expression level of various cytokines, this therapy can avoid immunogenicity during treatment. It has the potential to improve the safety and efficacy of mRNA-based therapeutics. By reducing the immune response to the therapy, it may be possible to deliver higher doses of mRNA and achieve better therapeutic outcomes. Further research is also needed to fully understand the potential of this approach and optimize its use in clinical settings.