Scientists Use New Protein Replacement Therapy to Treat Hemophilia B in Mice

Scientists have managed to treat hemophilia B in a mouse model of the disease, using a new method of protein replacement therapy. 

The findings appeared in Proceedings of the National Academy of Sciences, in the article, “Systemic delivery of factor IX messenger RNA for protein replacement therapy.”

The method uses a non-viral messenger RNA (mNA) delivery method, which remains effective longer than existing methods and creates virtually no immune response. mRNA is the transcript from human DNA code that is sent to the protein-making machinery of cells to produce proteins. 

“We are really excited about this work because, short of correcting a faulty gene, protein-replacement therapy using mRNA is one of the most promising techniques we have at our disposal,” the study’s senior author, Inder Verma of the Salk Institute for Biological Studies in La Jolla, California, said in a press release. “Now we have proof that we can successfully treat a disease with virtually no side effects at a lower cost than manufacturing the needed protein.”

The new method uses a “safe, reproducible, and effective mRNA delivery platform” called LUNAR that encapsulates the message (mRNA) encoding for the factor IX protein (the one that is mutated in hemophilia B patients) in fatty acid nanoparticles and injects it into the bloodstream. Once the complex reaches the liver, the fatty acid particles are broken down and the message is released. At that point, the cells’ protein-making machinery starts producing factor IX.

This is a much more effective method of replacing the body’s faulty factor IX protein than existing methods, in which factor IX is made in animal cells (called recombinant protein) and then directly injected into the body. This method can trigger an immune response, where antibodies attack the foreign factor IX protein and destroy it. The so-called recombinant factor IX is also expensive to produce and must be injected several times a week.

In the new method, the protein is made in a person’s own body, making it less likely for the body to trigger an immune response. It’s also easier and cheaper to produce mRNA compared to protein.

Researchers injected the human factor IX mRNA-LUNAR complex into mice with hemophilia B three times over a five-month period and carefully monitored the mice’s blood clotting and immune response. Normal blood clotting occurred within four hours of the injection and lasted for up to six days. Moreover, the injection only triggered a mild immune response that quickly disappeared.

“We gave the treatment over a long span to give the immune system time to see it and react to it, but the immune response looked more like a mild allergic response and quickly returned to normal, so the technology seems pretty reliable and safe in our mouse model,” Verma said.

Pad Chivukula, chief scientific officer at Arcturus Therapeutics, which collaborated in this work, added: ”Conceptually, in vivo mRNA delivery has been around for a long time, but its therapeutic use has been limited by poor stability, immune reactivity and problems with reproducible systemic delivery. The results suggest that nanoparticle delivery technology overcomes these challenges and might allow for the development of novel, cost-effective mRNA therapeutics.”

Results obtained in a mouse model may not exactly apply to humans, scientists warn. Nonetheless, the study proves the concept of using mRNA therapy to treat hemophilia B, as well as hemophilia A — which is caused by another faulty blood clotting factor called factor VIII — and other genetic conditions.