The inverted clitocybe, an edible mushroom found in the northern hemisphere, is at the center of research to identify ways to correct certain genetic mutations, known as nonsense mutations. It could open therapeutic perspectives against cystic fibrosis.
The Flaccid lepista – that’s its scientific name – is common in our latitudes, edible but rather tasteless. And this mushroom contains a promising molecule, 2,6-diaminopurine (DAP), which could be effective against rare genetic diseases and in particular the cystic fibrosis, the most frequent rare genetic pathology. As a reminder, this affects the cells that produce mucus, sweat or digestive juices: these fluids become thick, sticky, and clog the various channels or airways.
>> A video from INSERM explaining how cystic fibrosis works:
A French research team has just published his results in the journal Molecular Therapy: she tested this active ingredient in different experimental models of the disease. The inverted clitocybe enzyme acts on a particular mutation, known as the nonsense mutation in cystic fibrosis (read box): this modifies a DNA sequence in such a way that it cannot encode the desired protein which, therefore, is dysfunctional.
In 10% of cases of cystic fibrosis, treatments do not work because of this nonsense mutation: “The molecule has not yet been tested in humans, but we know how it can act within the cell” , notes Fabrice Lejeune, an INSERM researcher withinto OncoLthe Lille Cancer Institute, which brings together various organizations including the CNRS, the University of Lille, the Institut Pasteur and the Lille University Hospital.
>> Read also: New drug gives hope to CF patients
Hide the mutation and erase its consequences
“This molecule was purified from the fungus Flaccid lepista: it masks the nonsense mutation and erases its consequences, which makes it possible to restore a protein to the right size and function, at least in the models that we tested”, explains the first author of the study to the microphone of CQFD.
The DAP molecule was tested in mice, on the CFTR gene responsible for cystic fibrosis: “We obtained a functional restoration of this CFTR channel by giving these mice, every day, orally, DAP. We also tested on cells from patients with cystic fibrosis and on organoids, i.e. cells that assemble to mimic the characteristics of an organ. And, each time, we obtained a restoration of the expression of the CFTR channel, but also a functional restoration of it”, he underlines.
Concretely, the mice no longer expressed the symptoms of cystic fibrosis: “We erased a certain number of characteristics. In the mice, there is a mortality which is linked to the absence of the CFTR channel and we succeeded, by feeding the mothers to help save embryos in utero. We had a lot more births of babies with the mutation, for example. Then, we continued the treatment on these newborns.”
A very special library
A new therapeutic perspective which was born thanks to long research on nonsense mutations. Fabrice Lejeune discovered the inverted clitocybe in 2012 thanks to the Chemical library and Extract library of the Natural History Museum of Paris, a library of micro-organisms.
Initially, the researcher had no idea that this fungus could be of any use: “We started with what is called screening: a somewhat blind test of thousands of chemical compounds. I am from 20,000 extracts of plants, micro-organisms and fungi and only one gave us activity”. This is how the encouraging properties of Flaccid lepista.
Nonsense mutations exist in other rare diseases; in the future, researchers think that this molecule could be used to combat other pathologies.
Subject radio: Sarah Dirren
Web article: Stephanie Jaquet