RNA breakthrough makes it possible to cure Cystic Fibrosis with an inhaler

WHY THIS MATTERS IN BRIEF

A revolutionary new way to deliver mRNA into the body in aerosol form makes genetically editing faulty genes easier than ever before.

Recent there have been some almost miraculous medical breakthroughs, from treating patients with inherited genetic diseases with in vivo gene therapy treatments and 3D printing body parts, through to curing paralysis, growing brains in jars, and designing nanomachines that drill into diseased cells and kill them. Dead. And all of that is just for starters. Now though there’s been another breakthrough and its potential to change healthcare forever is potentially just as significant. Messenger RNA, which can induce cells to produce therapeutic proteins, holds great promise for treating a variety of diseases, but so far the biggest obstacle to this approach has been finding safe and efficient ways to deliver what’s known as mRNA molecules to the target human cells they’re intended to treat.

In an advance that could lead to new almost science fiction like treatments for lung disease researchers at MIT in the US have announced they’ve designed “an inhalable form of mRNA.” When put into an aerosol means you could cure a myriad of genetic disorders and diseases, such as Cystic Fibrosis, just by inhaling the new genetic cocktail using a standard inhaler or nebulizer.

“We think the ability to deliver mRNA via inhalation could allow us to treat a range of different diseases [especially] of the lung,” says Daniel Anderson, an associate professor in MIT’s Department of Chemical Engineering and the senior author of the study.

During the experiment 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 appeared in this months issue of the journal Advanced Materials.

Messenger RNA encodes genetic instructions that stimulate cells to produce specific proteins, and many researchers have been working on developing mRNA to treat genetic disorders and Cancer, by essentially turning the patients’ own cells into advanced drug factories – a trend that elsewhere other researchers are also zeroing in on by using DNA to turn patients bodies into nothing less than “disease fighting supercomputers.”

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 aerosol delivery phrase. Some previous studies have explored a material called Polyethylenimine (PEI) for delivering inhalable DNA to the lungs but PEI doesn’t break down easily, so with the repeated dosing that would likely be required for mRNA therapies, the polymer could end up accumulating in the patients body 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 consisted 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 their lung cells were producing the bioluminescent protein, which showed that their experiment had worked. The amount of protein then gradually fell over time as the mRNA was cleared but the researchers were able to maintain steady levels of the protein by giving the mice repeated doses, which may be necessary the treatment’s going to be used to treat chronic lung disease.

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.

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, and other sources of funding for this study include the UK Engineering and Physical Sciences Research Council and the Koch Institute Support Grant from the National Cancer Institute.