Nav: Home

Engineers create an inhalable form of messenger RNA

January 04, 2019

Messenger RNA, which can induce cells to produce therapeutic proteins, holds great promise for treating a variety of diseases. The biggest obstacle to this approach so far has been finding safe and efficient ways to deliver mRNA molecules to the target cells.

In an advance that could lead to new treatments for lung disease, MIT researchers have now designed an inhalable form of mRNA. This aerosol could be administered directly to the lungs to help treat diseases such as cystic fibrosis, the researchers say.

"We think the ability to deliver mRNA via inhalation could allow us to treat a range of different disease of the lung," says Daniel Anderson, an associate professor in MIT's Department of Chemical Engineering, a member of MIT's Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES), and the senior 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, that could be high enough to treat many lung diseases, the researchers say.

Asha Patel, a former MIT postdoc who is now an assistant professor at Imperial College London, is the lead author of the paper, which appears in the Jan. 4 issue of the journal Advanced Materials. Other authors of the paper include James Kaczmarek and Kevin Kauffman, both recent MIT PhD recipients; Suman Bose, a research scientist at the Koch Institute; Faryal Mir, a former MIT technical assistant; Michael Heartlein, the chief technical officer at Translate Bio; Frank DeRosa, senior vice president of research and development at Translate Bio; and Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute.

Treatment by inhalation

Messenger RNA encodes genetic instructions that stimulate cells to produce specific proteins. Many researchers have been working on developing mRNA to treat genetic disorders or cancer, by essentially turning the patients' own cells into drug factories.

Because mRNA can be easily broken down in the body, it needs to transported within some kind of protective carrier. Anderson's lab has previously designed materials that can deliver mRNA and another type of RNA therapy called RNA interference (RNAi) to the liver and other organs, and some of these are being further developed for possible testing in patients.

In this study, the researchers wanted to create an inhalable form of mRNA, which would allow the molecules to be delivered directly to the lungs. Many existing drugs for asthma and other lung diseases are specially formulated so they can be inhaled via either an inhaler, which sprays powdered particles of medication, or a nebulizer, which releases an aerosol containing the medication.

The MIT team set out to develop a material that could stabilize RNA during the process of aerosol delivery. Some previous studies have explored a material called polyethylenimine (PEI) for delivering inhalable DNA to the lungs. However, PEI doesn't break down easily, so with the repeated dosing that would likely be required for mRNA therapies, the polymer could accumulate and cause side effects.

To avoid those potential side effects, the researchers turned to a type of positively charged polymers called hyperbranched poly (beta amino esters), which, unlike PEI, are biodegradable.

The particles the team created consist of spheres, approximately 150 nanometers in diameter, with a tangled mixture of the polymer and mRNA molecules that encode luciferase, a bioluminescent protein. The researchers suspended these particles in droplets and delivered them to mice as an inhalable mist, using a nebulizer.

"Breathing is used as a simple but effective delivery route to the lungs. Once the aerosol droplets are inhaled, the nanoparticles contained within each droplet enter the cells and instruct it to make a particular protein from mRNA," Patel says.

The researchers found that 24 hours after the mice inhaled the mRNA, lung cells were producing the bioluminescent protein. The amount of protein gradually fell over time as the mRNA was cleared. The researchers were able to maintain steady levels of the protein by giving the mice repeated doses, which may be necessary if adapted to treat chronic lung disease.

Broad distribution

Further analysis of the lungs revealed that mRNA was evenly distributed throughout the five lobes of the lungs and was taken up mainly by epithelial lung cells, which line the lung surfaces. These cells are implicated in cystic fibrosis, as well as other lung diseases such as respiratory distress syndrome, which is caused by a deficiency in surfactant protein. In her new lab at Imperial College London, Patel plans to further investigate mRNA-based therapeutics.

In this study, the researchers also demonstrated that the nanoparticles could be freeze-dried into a powder, suggesting that it may be possible to deliver them via an inhaler instead of nebulizer, which could make the medication more convenient for patients.
-end-
TranslateBio, a company developing mRNA therapeutics, partially funded this study and has also begun 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 United Kingdom Engineering and Physical Sciences Research Council and the Koch Institute Support (core) Grant from the National Cancer Institute.

Related links

ARCHIVE:

New materials improve delivery of therapeutic messenger RNA

ARCHIVE:

CRISPR-carrying nanoparticles edit the genome

ARCHIVE:

Nanoparticle screen could speed up drug development

ARCHIVE:

Engineers design programmable RNA vaccines

Massachusetts Institute of Technology

Related Cystic Fibrosis Articles:

Rare mutations drive cystic fibrosis in Caribbean
Cystic Fibrosis (CF) in the Caribbean is dominated by unusual gene mutations not often observed in previously studied CF populations, according to comprehensive genome sequencing led by physician-scientists at UC San Francisco and Centro de Neumología Pediátrica in San Juan.
Cystic fibrosis carriers at increased risk of digestive symptoms
Researchers have found that carriers of the most common genetic variant that causes cystic fibrosis experience some symptoms similar to those of people with cystic fibrosis.
In cystic fibrosis, lungs feed deadly bacteria
A steady supply of its favorite food helps a deadly bacterium thrive in the lungs of people with cystic fibrosis, according to a new study by Columbia researchers.
Cibio knocks out cystic fibrosis
The fight against cystic fibrosis continues, targeting in particular some of the mutations that cause it.
Hypertonic saline may help babies with cystic fibrosis breathe better
Babies with cystic fibrosis may breathe better by inhaling hypertonic saline, according to a randomized controlled trial conducted in Germany and published in the American Thoracic Society's American Journal of Respiratory and Critical Care Medicine.
Understanding antibiotic resistance in patients with cystic fibrosis
Patients with cystic fibrosis who carried antibiotic-resistant bacteria in their lungs had significantly lower microbial diversity and more aggressive disease, according to a small study published in Heliyon.
Research shows that cystic fibrosis impacts growth in the womb
New research, published in Thorax, funded by the Cystic Fibrosis Trust has shown that babies with cystic fibrosis (CF) are born weighing less than babies without the condition, even allowing that they are more likely to be born prematurely.
Discovery gives cystic fibrosis researchers new direction
A multi-disciplinary team of researchers at the Novartis Institutes for BioMedical Research (NIBR) and Harvard Medical School (HMS) started out trying to catalogue all the different cells in the airway and the paths they take to become those cells.
Supplemental antioxidants may reduce exacerbations in cystic fibrosis
An antioxidant-enriched vitamin may decrease respiratory exacerbations in people with cystic fibrosis (CF), according to new research published online in April in the American Journal of Respiratory and Critical Care Medicine.
Protein structure could unlock new treatments for cystic fibrosis
Biochemists at the University of Zurich have used cryo-electron microscopy to determine the detailed architecture of the chloride channel TMEM16A.
More Cystic Fibrosis News and Cystic Fibrosis Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

Accessing Better Health
Essential health care is a right, not a privilege ... or is it? This hour, TED speakers explore how we can give everyone access to a healthier way of life, despite who you are or where you live. Guests include physician Raj Panjabi, former NYC health commissioner Mary Bassett, researcher Michael Hendryx, and neuroscientist Rachel Wurzman.
Now Playing: Science for the People

#544 Prosperity Without Growth
The societies we live in are organised around growth, objects, and driving forward a constantly expanding economy as benchmarks of success and prosperity. But this growing consumption at all costs is at odds with our understanding of what our planet can support. How do we lower the environmental impact of economic activity? How do we redefine success and prosperity separate from GDP, which politicians and governments have focused on for decades? We speak with ecological economist Tim Jackson, Professor of Sustainable Development at the University of Surrey, Director of the Centre for the Understanding of Sustainable Propserity, and author of...
Now Playing: Radiolab

An Announcement from Radiolab