Nature Communications: Not only vaccines, mRNA technology can also treat rare genetic diseases

Glycogen storage disease 1a (GSD1a) is a rare inherited metabolic disorder caused by glucose 6-phosphatase (G6Pase-α) deficiency.

Compared with traditional methods, it has considerable advantages to restore protein function by delivering mRNA to tissues.

Despite the many benefits, the lack of effective and safe delivery methods has hindered the advancement of clinically based mRNA therapies.

On May 25, 2021, the rare disease research team of Moderna Inc.

The research team demonstrated the effectiveness and safety of using lipid nanoparticles (LNP) to deliver engineered mRNA in a mouse model of glycogen storage disease, and proposed a method that may have a significant impact on the treatment of glycogen storage disease.

In order to ensure effective mRNA performance in vivo, the research team optimized mRNA and protein sequences.

Next, the research team evaluated the subcellular localization of the exogenous hG6Pase-α_S298C variant protein.

In order to evaluate the effect of optimized hG6PC S298C mRNA on the liver, the research team measured the transcript and protein activity of hG6PC S298C over time and found that compared with unoptimized mRNA, optimized hG6PC mRNA can lead to higher liver hG6Pase-α protein Levels and enzymatic activity.

In order to evaluate the in vivo efficacy of hG6PC S298C mRNA, the research team injected hG6PC S298C mRNA into a mouse model that mimics the clinical phenotype of GSD1a patients.

Safety is a key factor to be considered in the development of any drug therapy.

Finally, the research team delivered hG6PC S298C mRNA to mice with liver cancer, and found that the tumor size in the treatment group was smaller, and the plasma concentration of alpha-fetoprotein, which symbolizes the progression of liver cancer, was also significantly reduced, indicating that long-term hG6PC S298C mRNA treatment can reduce the risk of liver cancer progression.

In this study, the research team designed chemically modified co-mRNAs-α encoding hG6Pase and encapsulated them in lipid nanoparticles (LNP) for delivery to the liver.

This is also the first evidence that repeated administration of mRNA-based GSD1a drug therapy in a preclinical mouse model can improve fasting tolerance and the risk of liver disease.

Original source:

Cao, J.