Genetic therapies have long been seen as having great potential, but have been difficult to achieve in practice. The concept generally involves using the body’s own refined systems for generating proteins to build large and complex molecules to treat diseases that resist conventional drugs, by inserting customised stretches of genetic code into the nuclei of cells in affected tissues. One problem has been that the immune system resists such invasion. The MIT team, at the Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science, has designed an inhalable form of messenger RNA (mRNA) that could be administered directly to the lungs to treat diseases like cystic fibrosis.
In the body, mRNA conveys genetic information from DNA, the medium that encodes all genetic information, to the ribosome, the molecular machine inside living cells where proteins are synthesised. In genetic therapy, it is the most common medium used to try to “trick” cells into making therapeutic proteins. The problem for genetic engineers has so far been to find safe and efficient ways to deliver mRNA into target cells. It is easily broken down within the body, so needs to be transported inside some kind of protective carrier. The MIT team has been working on materials to stabilise RNA during aerosol delivery, so that it can be inhaled in the same way that asthmatics inhale drugs like salbutamol.
“We think the ability to deliver mRNA via inhalation could allow us to treat a range of different diseases of the lung,” said 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 a paper on the study.
Working with renowned gene therapy pioneer Robert Langer, a team including Anderson and Asha Patel, who has since moved to Imperial College London, took as a starting point a material called polyethylenimine (PEI) which has previously been investigated for delivering inhalable DNA. However, PEI does not break down easily and tends to accumulate, especially as mRNA therapy would need to consist of accumulative doses. The researchers switched to a type of positively charged polymer called hyper- branched poly (beta amino esters), which are biodegradable.
In a paper in Advanced Materials, the team describes how it tested its technique by encapsulating a stretch of mRNA that encoded a fluorescent protein called luciferase, found in fireflies and marine animals, and seeing if it could be expressed in the lungs of mice. The researchers synthesised spherical particles around 150nm in diameter consisting of a tangled mixture of the delivery esters and experimental mRNA. These were suspended in liquid droplets which they delivered to the mice via a nebuliser as an inhalable mist. They found that 24 hours later luciferase was produced inside the mice’s lungs, in quantities that gradually fell over time. Repeated doses maintained a steady level of the protein.
Luciferase was produced particularly by epithelial lung cells, which line the inner surfaces of the organ and are implicated in cystic fibrosis and the condition called respiratory distress syndrome, which is caused by a deficiency in a protein which acts as a surfactant in lung tissues.
The MIT team also demonstrated that the nanoparticles could be freeze dried into a powder which could theoretically be delivered via a conventional inhaler rather than the more bulky and awkward nebuliser. Dr Patel is planning to further investigate mRNA-based therapeutics at Imperial. Back in the US, another co-founder, TranslateBio, has begun an early-stage clinical trial of inhalable mRNA for cystic fibrosis.
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