An inhalable form of mRNA for the treatment of lung diseases
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An inhalable form of mRNA for the treatment of lung diseases

An inhalable form of mRNA for the treatment of lung diseases

About 80 RNA therapeutics are currently in clinical trial. Among these drug candidates, mRNA, 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. MIT researchers have now designed an inhalable form of mRNA that could lead to new treatments for lung diseases. This aerosol could be administered directly to the lungs to help treat diseases such as cystic fibrosis. The researchers showed that they could induce lung cells in mice to produce a target protein – in this case, luciferase, a bioluminescent protein. 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.

A new material to stabilize mRNA

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. These particles have been suspended in droplets and delivered to mice as an inhalable mist, using a nebulizer. 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.

  • MIT researchers have designed inhalable particles that can deliver messenger RNA. These lung epithelial cells have taken up particles (yellow) that carry mRNA encoding green fluorescent protein. ©Asha Patel

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, Asha Patel, the lead author of the paper, now 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.

Clinical trial for cystic fibrosis

TranslateBio, a company developing mRNA therapeutics, partially funded this study and has also begun testing an inhalable form of mRNA, MRT5005, in a Phase 1/2 clinical trial in patients with cystic fibrosis. MRT5005 is delivering mRNA encoding fully functional cystic fibrosis transmembrane conductance refulator (CFTR) to the lung epithelial cells through nebulization. So it could be used to treat all patients with cystic fibrosis, regardless of the underlying geneti mutation, including those with limited or no CFTR protein.  First patient dosing is anticipated in early 2019 and the company anticipates reporting interim data for tis trial in the second half of 2019. TranslateBio has also adanced MRT5201, its second mRNA product candidate towards the clinic.  This mRNA is encoding the fully functional ornithine transcarbamylase enzyme and will be used to treat patients with ornithine transcarbamylase deficiency (OTC), the most common urea cycle disorder. Screening of patients with OTC deficiency is anticipated in the first half of 2019 in the US. Both compounds have been granted orphan drug designation in the US.

This paper appears in the Jan. 4 issue of the journal Advanced Materials. (Inhaled Nanoformulated mRNA Polyplexes for Protein Production in Lung Epithelium 2019 Jan 4. Patel AK, Kaczmarek JC, Bose S, Kauffman KJ, Mir F, Heartlein MW, DeRosa F, Langer R, Anderson DG. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. TranslateBio, Lexington, MA, 02421, USA.