MHH researchers introduce mRNA with a building block for telomerase into human lung cells to reduce ageing processes and fibrosis development.
Investigated how preserving the protective caps for our genetic material can improve lung health: molecular biologist Dr Shambhabi Chatterjee (right) and lead author Dr Jia Li Ye. Copyright: Karin Kaiser/MHH
Pulmonary fibrosis – also known in technical terms as idiopathic pulmonary fibrosis (IPF) – is a rare but life-threatening disease. It causes scarring of the connective tissue between the functional tissue of the lungs, leading to increasing shortness of breath. Current treatments can slow the progression of fibrosis, but cannot cure it. The average life expectancy after diagnosis is only four to six years. New therapies are therefore urgently needed. A research team led by Professor Christian Bär, research group leader at the Institute for Molecular and Translational Therapy Strategies at Hannover Medical School (MHH), and his colleague Dr Shambhabi Chatterjee has turned its attention to the interior of cells, or more precisely to telomeres. These are protective caps at the ends of chromosomes, the carriers of our genetic information.
With each cell division, the telomeres shorten a little until they reach a critical length and the genes they protect could be damaged. Then the cell stops dividing and the tissue ages. In people with pulmonary fibrosis, this process often occurs faster than normal. Researchers therefore see a promising therapeutic approach in the enzyme telomerase, which protects telomeres from damage and shortening during cell division. In a study, they increased telomerase activity in human lung cells and lung tissue, thereby significantly reducing cell ageing and fibrosis development. The results have been published in the journal ‘Aging Cell’. The lead author is Dr Jia Li Ye.
Risk factor: shortened telomeres
Professor Bär and Dr Chatterjee have long been studying the role of telomerase in connection with diseases. They have discovered that administering telomerase in mouse models significantly extends the lifespan of even adult and aged animals and has a protective effect on the heart even after a heart attack. They have now investigated how this therapeutic approach could work in the lungs. This is because one risk factor for IPF is the premature shortening of telomeres in the lungs. Telomerase, or more precisely its subunit called telomerase reverse transcriptase (TERT), which lengthens telomeres during embryonic development, plays a crucial role here. Since TERT is usually switched off in adult humans, this enzyme cannot protect the ends of chromosomes and thus also the DNA. The researchers have now investigated whether a biomedically generated excess of telomerase could have a positive effect on telomere length and thus on the disease.
Precision lung sections from fibrotic tissue
To do this, they introduced messenger RNA (mRNA) containing the TERT blueprint into connective tissue cells in the human lung. ‘We could see that our mRNA was working and that the cells were reading and implementing the blueprint,’ says Professor Bär. ‘Telomerase was activated, the ageing biomarkers decreased and the telomeres of the chromosomes were lengthened again.’ In cell cultures with lung precursor cells, the cells also produced TERT for telomerase activation. The therapeutic approach even worked in human pulmonary fibrosis tissue. In collaboration with the Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, special precision lung sections (PCLS) were produced from surgically removed patient material and treated with TERT mRNA. ‘Here, too, the markers for ageing and fibrosis improved significantly,’ says Dr Chatterjee. ‘In addition, the inflammation markers declined, which means that our TERT mRNA works and the mRNA structure itself did not trigger a harmful immune response.’
Modified RNA tricks the immune system
This was achieved because the researchers inserted the TERT blueprint into a modified mRNA (modRNA). Unlike the mRNA normally found in the body, this is very slightly altered. This allows it to be smuggled into the body without alerting it and causing inflammatory reactions. This is because our immune system actually recognises foreign RNA and prevents it from entering and being converted – for example, to defend against viruses. ModRNA technology has already been used successfully during the coronavirus pandemic to develop the COVID-19 vaccine. One advantage of the process is that this foreign component enters the cells but not the cell nucleus and remains in the body for only a few days. ‘This makes the technology much safer than conventional gene therapies, in which the genes are introduced directly into the body and remain there permanently,’ notes Professor Bär.
Circular RNA expands therapeutic window
However, its short retention time also means that the introduced blueprint can only be implemented for a short period of time. In order to further expand the therapeutic window, the researchers modified the mRNA once again and closed the RNA strand into a ring. ‘This circular RNA cannot be destroyed as quickly by the degradation enzymes,’ explains Dr Chatterjee. The slowed degradation ensures that there is more telomerase in the cells compared to linear RNA, making it more effective. ‘According to our results, TERT therapy is a promising approach to improving the health of lung cells and slowing down and perhaps even reversing the development of fibrosis,’ says Professor Bär. Packaged in lipid nanoparticles, the therapeutic RNA could eventually be simply inhaled.
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The original paper, ‘Telomerase modRNA Offers a Novel RNA-Based Approach to Treat Human Pulmonary Fibrosis,’ can be found here.
Text: Kirsten Pötzke