Lab mouse
Researchers have reported the successful treatment of hemophilia B in mice using messenger RNA (mRNA).
In experiments, protein-replacement therapy using mRNA was effective longer than recombinant factor IX (FIX) therapy.
The mRNA therapy also appeared to be safe and produced mild, transient immune responses.
In addition, the researchers noted that the mRNA therapy can be produced more cheaply than recombinant FIX therapy.
They said this research, published in PNAS, is proof-of-concept that mRNA therapy could be used to treat hemophilia B and other genetic diseases.
“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,” said study author Inder Verma, PhD, of the Salk Institute for Biological Studies in La Jolla, California.
“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.”
This work is a collaboration between the Verma lab and Arcturus Therapeutics, a biotech company that developed a system of encapsulating mRNA within lipid nanoparticles.
The researchers created an mRNA blueprint for human FIX nanoparticles and delivered them, via injection, to mice with a faulty FIX gene.
Once in the bloodstream, the nanoparticles traveled to the liver, where their fatty casing helped them ease into cells and deliver to the protein-making machinery the mRNA instructions to assemble FIX.
The hemophilic mice were given 3 injections over a 5-month period, during which their coagulation and immune responses were carefully monitored.
Normal clotting occurred in the mice within 4 hours of receiving the therapy, and the results lasted for up to 6 days.
The mice had a weak immune response to the treatment, which quickly returned to baseline.
“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 study author Suvasini Ramaswamy, PhD, of the Salk Institute for Biological Studies.
“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.”
The researchers also gave mice recombinant FIX, directly comparing it to the mRNA therapy. The mRNA therapy proved more effective, maintaining 20% more clotting activity 4 days after injection.
“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, chief scientific officer 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.”
This work was funded by the National Institutes of Health, the Ipsen Foundation, the H.N. and Frances C. Berger Foundation, the Glenn Center for Research on Aging, The Leona M. and Harry B. Helmsley Charitable Trust, and the California Institute for Regenerative Medicine. The lipid nanoparticles were developed by Arcturus Therapeutics.
