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:

Cystic fibrosis alters the structure of mucus in airways
Cystic fibrosis (CF) alters the structure of mucus produced in airway passages.
Cystic fibrosis study offers new understanding of silent changes in genes
Researchers studying the root cause of cystic fibrosis have made a major advance in our understanding of silent gene changes with implications for the complexity of cystic fibrosis.
New imaging technique shows effectiveness of cystic fibrosis drug
Cystic fibrosis currently has no cure, though a drug approved by the Food and Drug Administration treats the underlying cause of the disease.
New study resolves the structure of the human protein that causes cystic fibrosis
In order to better understand how genetic mutations give rise to cystic fibrosis, researchers need to map the protein responsible for the disorder.
New molecules identified that could help in the fight to prevent cystic fibrosis
New research has identified new molecules that could help in the fight to prevent diseases caused by faulty ion channels, such as cystic fibrosis.
Newborn screening for cystic fibrosis
A new study led by a team from the Research Institute of the McGill University Health Centre and Cystic Fibrosis Canada reinforces the benefits of newborn screening for cystic fibrosis (CF) patients.
Evolving insights into cystic fibrosis lung infections
Recent research progress into how bacteria adapt and evolve during chronic lung infections in cystic fibrosis patients could lead to better treatment strategies being developed, according to a new review by the University of Liverpool.
Key hurdle overcome in the development of a drug against cystic fibrosis
In people suffering from cystic fibrosis the CFTR protein is not located in the right place in mucus-producing cells: it remains inside the cell while it should be in the cell wall.
Researchers further illuminate pathway for treatment of cystic fibrosis
By studying alveolar macrophages, which provide our airways with a crucial defense against pathogens, UNC scientists are now able to more fully understand the larger picture of CF symptoms and continue progress towards targeted treatments, aside from addressing the mutated CFTR gene.
Gene therapy: A promising candidate for cystic fibrosis treatment
An improved gene therapy treatment can cure mice with cystic fibrosis (CF).

Related Cystic Fibrosis Reading:

Hodson and Geddes' Cystic Fibrosis
by Andrew Bush (Editor), Diana Bilton (Editor), Margaret Hodson (Editor)

Handbook of Cystic Fibrosis
by Amy G. Filbrun (Author), Thomas Lahiri (Author), Clement L Ren (Author)

Nutrition in Cystic Fibrosis: A Guide for Clinicians (Nutrition and Health)
by Elizabeth H. Yen (Editor), Amanda Radmer Leonard (Editor)

Cystic Fibrosis: A Guide for Patient and Family
by David M. Orenstein MD (Author), Jonathan E. Spahr MD (Author), Daniel J. Weiner MD (Author)

Cystic Fibrosis (ORML) (Oxford Respiratory Medicine Library)
by Alex Horsley (Editor), Steve Cunningham (Editor), J Alastair Innes (Editor)

Cystic Fibrosis (Genes & Disease)
by Sharon Giddings (Author)

There Are No Alligators in Heaven!: A family's perspectives on surviving the unrelenting savagery of Cystic Fibrosis
by Donna Codell (Author), Evan Michael Codell (Author), Jennifer Hale (Author)

Breathing Bravely: Giving Voice to Cystic Fibrosis
by Ashley Ballou Bonnema (Author), Paige Pearson Meyer (Editor)

Walter and the Mucous Monsters: A tale of adventure and Cystic Fibrosis
by Katherine Hitch (Author), Glenn Smith (Illustrator), Pip Valentine (Illustrator)

Changing Fate
by Michelle Merrill

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Approaching With Kindness
We often forget to say the words "thank you." But can those two words change how you — and those around you — look at the world? This hour, TED speakers on the power of gratitude and appreciation. Guests include author AJ Jacobs, author and former baseball player Mike Robbins, Dr. Laura Trice, Professor of Management Christine Porath, and former Danish politician Özlem Cekic.
Now Playing: Science for the People

#509 Anisogamy: The Beginning of Male and Female
This week we discuss how the sperm and egg came to be, and how a difference of reproductive interest has led to sexual conflict in bed bugs. We'll be speaking with Dr. Geoff Parker, an evolutionary biologist credited with developing a theory to explain the evolution of two sexes, about anisogamy, sexual reproduction through the fusion of two different gametes: the egg and the sperm. Then we'll speak with Dr. Roberto Pereira, research scientist in urban entomology at the University of Florida, about traumatic insemination in bed bugs.