The RNA messenger, which can induce cells to produce therapeutic proteins, promises a great promise to treat a variety of diseases. The biggest obstacle to this approach was finding safe and effective ways to supply mRNA molecules to the target cells.
In an advance that could lead to new treatments for pulmonary disease, MIT researchers have now designed an inhalable form of mRNA. This aerosol could be given directly to the lungs to help treat diseases such as cystic fibrosis, researchers say.
"We believe that the ability to deliver mRNA through inhalation could allow us to treat a number of different lung conditions," says Daniel Anderson, Associate Professor at the MIT's Chemistry Department, a member of the Koch MITs Institute for Integrative Cancer Research and the Institute of Engineering Medical and Science (IMES), and lead author of the study.
The researchers showed that they could induce lung cells in mice to produce a target protein – in this case, a bioluminescent protein. If the same success rate can be achieved with therapeutic proteins, which could be big enough to treat many lung diseases, the researchers say.
Asha Patel, former post-doctoral MIT, who is now an assistant professor at Imperial College London, is the lead author of the paper, which appears in the January 4 issue of the magazine Advanced materials. Other authors of the paper include James Kaczmarek and Kevin Kauffman, both recipients of MIT PhD students; Suman Bose, scientific researcher at the Koch Institute; Faryal Mir, former MIT technical assistant; Michael Heartlein, Technical Director at Bio Translation; Frank DeRosa, senior vice president of research and development at Bio Translation; and Robert Langer, professor at the David H. Koch Institute at MIT and member of the Koch Institute.
The RNA messenger encodes the genetic instructions that stimulate cells to produce specific proteins. Many researchers have been working on the development of mRNA to treat genetic disorders or cancer, essentially turning their own patients' cells into drug factories.
Because mRNA can be easily degraded in the body, it should be transported in some kind of protective support. Anderson's lab has previously designed materials that can supply mRNA and another type of RNA therapy called RNA interference (RNAi) with the liver and other organs, and some of these are further developed for possible patient tests.
In this study, the researchers wanted to create an inhalable form of mRNA, which would allow molecules to be delivered directly to the lungs. Many existing bronchial asthma and other lung diseases are formulated specifically so that they can be inhaled either by an inhaler, which sprays powdered drug particles, or a nebulizer that releases an aerosol containing the drug.
The MIT team has set out to develop a material that could stabilize RNA during the aerosol delivery process. Some previous studies have explored a material called polyethyleneimine (PEI) for the release of inhalable DNA into the lungs. However, PEI does not readily break down, so with repeated dosing likely to be needed for mRNA the polymer may accumulate and cause side effects.
To avoid these potential side effects, researchers have turned into a type of positively charged polymers called poly (beta amino esters) hyperbranched, which, unlike PEIs, are biodegradable.
The particles the team created consist of spheres of about 150 nanometers in diameter with a tangled mixture of polymer molecules and mRNA encoding luciferase, a bioluminescent protein. Researchers suspended these particles in drops and delivered them to mice as an inhalable mist using a nebulizer.
"Breathing is used as a simple but effective way to administer the lungs. Once the aerosol droplets are inhaled, the nanoparticles contained in each drop enter the cells and train it to make a certain protein from the mRNA," says Patel.
The researchers found that 24 hours after the mice inhaled mRNA, the lung cells produced the bioluminescent protein. The amount of protein gradually decreased, while mRNA was eliminated. The researchers were able to maintain constant protein levels by giving repeated dose mice that may be needed if they are adapted to treat chronic pulmonary disease.
Lateral lung analysis showed that mRNA was evenly distributed in the five lobes of the lungs and was mainly taken up by epithelial pulmonary cells that align the lung surfaces. These cells are involved in cystic fibrosis, as well as other lung diseases such as respiratory distress syndrome, which is caused by a deficiency of the surfactant protein. In his new lab at the Imperial College in London, Patel plans to further investigate mRNA-based therapy.
In this study, the researchers also demonstrated that nanoparticles could be freeze-dried in a powder, suggesting that they could be delivered via an inhaler instead of a nebulizer, which could make the medicine more convenient for patients .
TranslationBio, a company that develops mRNA therapy, partially funded this study and also began testing an inhalable form of mRNA in a Phase 1/2 clinical trial in patients with cystic fibrosis. Other sources of funding for this study include the UK's Engineering and Physical Sciences Research Council and the Koch Institute Support (Basic) Grant from the National Cancer Institute.