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Biochemically modified messenger RNA encoding nucleases for in vivo gene correction of severe inherited lung diseases

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Modified mRNA and gene editing show promise to treat lung diseases

Lung diseases like cystic fibrosis reduce quality of life and lead to early death. An innovative approach to gene therapy could help sufferers and may also bolster the immune system against cancer and COVID-19.


Cystic fibrosis (CF) and surfactant protein B (SP-B) deficiency are fatal lung diseases. In the former, mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator protein result in thick secretions which cause breathing difficulties and frequent lung infections. The condition affects more than 70 000 people worldwide. SP-B deficiency leads to rapid fatal respiratory failure within the first year of life, due to mutations in the SP-B encoding genes. Attempts to use gene therapy, delivered to the relevant cells to treat these conditions, have been foiled by the lungs’ defence mechanism. This acts as a barrier to the direct delivery of treatments. Either therapies have not been able to reach target cells, or the desired reaction in the target cells has not been strong enough. The EU-supported BREATHE project investigated more unconventional, RNA-based therapeutic methods. The team was inspired by work done previously by BREATHE project coordinator, Michael Kormann. This highlighted the positive impact of modifying supplementary mRNA in SP-B deficient mice. During the project, researchers delivered chemically modified mRNA to cells within the trachea. This, as a compound formed with nanoparticles, led to gene correction of a partial lung cell in SP-B deficient mice. The Kormann lab (website in German) which hosted the project, recently used mRNA therapy successfully for the treatment of CF. The lab has also had success with gene correction therapy. “Our lab was the first to demonstrate not only that the application of modified mRNA intravenously leads to normal lung function, but also that gene editing of SP-B mice extends their life span significantly,” explains Kormann. Patents have already been granted for mRNA supplementation and mRNA-based gene correction, and others are pending for engineered RNA-only gene editing for use in patients.

Cutting-edge findings

The support from the European Research Council enabled the team to investigate the lung mechanics of mice using the flexiVent system. This accurately measures specific parameters of lung function, such as forced expiratory volume. Many of the results have already been made available. For example, the team has published the results of experiments to find highly active mRNA encoding for the protein ‘Cas9’, that can be administered repeatedly without provoking an immune response. This is significant as the mRNA delivers all components needed for gene correction, meaning multiple applications of the treatment might be required. “This is itself a small breakthrough for gene correction in the body,” notes Kormann. Linked to this, the lab has also published findings from enzyme-linked immunosorbent assay (ELISA) tests used to assess the ability of mRNAs to provoke immune responses. These tests incubate human blood samples revealing patterns of small proteins released by the immune system called cytokines.

A wide range of applications

“When used for encoding gene editing components, our optimisations create powerful, versatile tools for a wide variety of therapies. Beyond genetic lung diseases, such as CF, chronic obstructive pulmonary disease (COPD) and asthma, they have potential to prime immune cells to fight targets like cancer cells or even viral infections such as COVID-19,” says Kormann. The next step would be to demonstrate the technique’s efficacy in terminally ill CF patients. Towards this end, the team is seeking additional funding, while also planning to further explore the possibilities of RNA-based gene editing to enhance the immune system.


BREATHE, gene, cystic fibrosis, protein, surfactant protein B, deficiency, respiratory, RNA, immunosorbent, nanoparticles, COVID-19

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