New Inhaled Carrier May Work for CF mRNA Therapy, Mouse Study Finds

An inhaled form of messenger RNA (mRNA) with the potential to safely deliver therapeutics to the lungs of cystic fibrosis (CF) patients has been discovered by researchers at the Massachusetts Institute of Technology (MIT).

Researchers developed a type of nanoparticle given as an inhaled mist (nebulizer) that allows the delivery of mRNAs to the lungs of mice. This kind of carrier may be used to administer mRNA therapeutics directly to the lungs of people with CF and other lung diseases, researchers say.

The study with that finding, “Inhaled Nanoformulated mRNA Polyplexes for Protein Production in Lung Epithelium,” was published in the journal Advanced Materials.

Messenger RNA (mRNA) is the messenger molecule that converts the information from genes into a form that cells can “read” to produce a protein. Many research groups have been dedicated to develop ways to use mRNA coding for therapeutic proteins as a therapy for genetic disorders or cancer.

The major difficulty of this approach has been to find materials that are safe and efficient in delivering the mRNA molecules to target cells. mRNA molecules are typically very unstable and easily degradable, therefore they need to be transported by some form of protective carrier.

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In their study, researchers set out to create a carrier that would overcome these obstacles, and enable direct targeting to the lungs. Many medications for lung diseases, including CF, can be delivered via an inhaler, which sprays powdered particles of the drug to the lungs, or a nebulizer, that administers medication in the form of an inhaled mist.

The MIT team created very small spheres, or nanoparticles, of a polymer called hyperbranched poly (beta amino esters) that meshed with the mRNA. These polymers were able to stabilize the mRNA molecules during the delivery process and, importantly, they are biodegradable (naturally broken down). This is an important property, as the testing in humans of another promising carrier have been precluded due to concerns of toxicity caused by its accumulation in the body.

“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,” Asha Patel, PhD, lead author of the study, said in a MIT news release written by Anne Trafton. Patel is a former MIT researcher and professor at Imperial College London.

To perform the first preliminary and preclinical tests, researchers administered mice with mRNAs that code for the production of a protein that glows (the luciferase protein of fireflies). This approach allowed the scientists to use a light detector and a microscope to see which cells and organs took up the mRNAs and were producing the protein.

Results showed that 24 hours after mRNA delivery via nebulization, the molecules had reached the whole lungs and entered mainly epithelial cells, the ones that line lung surfaces and are involved in CF and other lung diseases.

Protein levels could be maintained constant by giving mice repeated doses of the mRNA-polymer product, a type of regimen that may be necessary if the drug is to be used for chronic lung diseases. Of note, the repeated administrations were not toxic to the animals.

The data also showed that delivery via an inhaler may be possible in the future, instead of a nebulizer, which could make the medication more convenient for patients.

Translate Bio, a company developing mRNA therapeutics has contributed to this study. Last year, the company launched a Phase 1/2 clinical trial (NCT03375047) to test the safety and tolerability of its inhaled mRNA therapy candidate for CF, MRT5005.

MRT5005 is administered via nebulization, and is designed to deliver mRNAs that instruct for the production of a fully functional CFTR protein, the faulty protein in CF. The product is designed to treat all CF patients, regardless of the type of mutations they carry.