Potential Hemophilia B Therapy Shows Promising Results in Mouse Study

Potential Hemophilia B Therapy Shows Promising Results in Mouse Study

A new delivery mechanism of mRNA therapy was found to efficiently reduce hemophilia B symptoms by correcting the protein deficiency that characterizes the disease in a mouse study. This potential new method might be a viable alternative for many clotting disorders.

The study, “Systemic delivery of Factor IX messenger RNA for protein replacement therapy,” was recently published in the Proceedings of the National Academy of Sciences.

Hemophilia B is caused by genetic mutations that occurs in the gene that encodes coagulation factor IX (FIX), which results in abnormal blood clotting. Standard care for these patients consists of injections into the bloodstream of plasma-derived or recombinant human FIX protein (rhFIX). These are expensive treatments that are 90 percent efficient in stopping hemorrhages but can also have serious side effects and complications.

Researchers from the Salk Institute in La Jolla, California, in collaboration with the San Diego biotech company Arcturus Therapeutics, showed that efficient delivery of RNA molecules that encode the functional human FIX gene can be achieved using a lipid nanoparticle (LNP) system called LUNAR, with fewer side effects than those of existing treatments — along with reduced production-associated costs.

“We are really excited about this work because, short of correcting a faulty gene, protein-replacement therapy using mRNA [messenger RNA, the molecule that leads to the production of the functional protein] is one of the most promising techniques we have at our disposal,” senior author Inder Verma said in a news 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 research team injected LUNAR carrying the human FIX mRNA into mice with hemophilia B. The nanoparticles traveled to the liver where the lipids of the capsule helped them ease into the cells and deliver the genetic material needed to assemble the correct form of the FIX protein. For five months the mice received three injections and their response to the treatment was carefully monitored.

Within four to six hours of receiving the therapy, the mice showed a normal clotting process, which remained stable for up to six days. The effectiveness of this therapeutic process was better than with standard care and with fewer side effects. Indeed, this mRNA therapy maintained 20 percent more clotting activity four days after injection than the rhFIX protein.

“One of the issues with both nanoparticles and mRNA treatment is toxicity, and in our study we did not see much evidence of that,” said Suvasini Ramaswamy, first author of the article. “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.”

This study also showed that mRNA therapy has the potential to be applied to several other genetic diseases, especially those that need to recover a protein’s biological activity.

“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,” said Pad Chivukula, CSO at Arcturus Therapeutics. “The results suggest that nanoparticle delivery technology overcomes these challenges and might allow for the development of novel, cost-effective mRNA therapeutics.”

These results need to be confirmed in humans, since the effects may not be exactly the same. Still, they suggest the potential for mRNA therapy for other human diseases.

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