Lepista flaccida, an edible mushroom found in the northern hemisphere, was the focus of research by French teams into ways of correcting certain genetic mutations known as nonsense mutations. © MNHN/CNRS – Christine Bailly

A molecule obtained from an edible mushroom could open up therapeutic avenues for patients with cystic fibrosis, the most frequent rare genetic disease. A team led by Fabrice Lejeune, Inserm researcher at the Cancer Heterogeneity, Plasticity and Resistance to Therapies laboratory[1] (Inserm/ CNRS/ Université de Lille/Institut Pasteur de Lille/University Hospital Lille) tested the effects of 2,6-diaminopurine (DAP), one of the active principles contained in the Lepista flaccida mushroom, in different experimental models of the disease.  The scientists have shown that this molecule could be of therapeutic value in patients with cystic fibrosis linked to a particular type of mutation known as a nonsense mutation. Their findings have been published in Molecular Therapy.

Around 6,000 people in France have cystic fibrosis, a genetic disease that primarily affects digestive and respiratory function, and has a 40 to 50-year life expectancy. Nevertheless, therapeutic innovations have improved patient prognosis in recent years. Treatments are now available for the vast majority of patients – those whose disease is caused by the delta F508 mutation of the CFTR gene. In these patients, the CFTR protein (coded by the CFTR gene) is present in small amounts but is dysfunctional. The molecules currently available are able to correct this dysfunction and significantly improve their clinical symptoms.

However, they are not effective in the 10% of patients for whom the protein is completely absent, as is the case when the disease is linked to a nonsense mutation (see box).

Identifying ways to correct nonsense mutations is therefore an important challenge for researchers studying genetic diseases and who hope to develop new therapeutic options against cystic fibrosis.

In this context, Inserm researcher Fabrice Lejeune and his team[2] made an innovative finding in 2017 by showing that extracts of a commonplace edible mushroom known as Lepista flaccida could repair nonsense mutations in three cell lines isolated from cystic fibrosis patients. A few years later in 2020, Lejeune and his team published a study identifying the active principle in the mushroom that is capable of correcting the nonsense mutations associated with the UGA stop codon – the most common of the three stop codons of the human genetic code. The active principle concerned was 2,6 diaminopurine (DAP).

In their latest research, the scientists tested the effects of this molecule in four experimental models of cystic fibrosis: animal models of the disease, developed in the laboratory; cell lines; patient cells and organoids. This diversity of models makes it possible to be as close as possible to what is happening in the patient’s body, in order to assess the potential therapeutic benefits they may obtain.

The results obtained by the team suggest that DAP corrects the nonsense mutation in the different models studied, by re-establishing protein production and effectively restoring the function of the mutated gene.

In clinical terms, this results in an improvement in symptoms in animals. The treatment with DAP makes it possible to restore CFTR expression in the lungs and intestines as well as the function of this protein, significantly reducing the premature mortality observed prior to administration of this molecule.

In addition, the research team has also shown that DAP can be given orally and that it is distributed effectively throughout the body for around two hours. These characteristics are also a positive point when it comes to considering DAP as a serious therapeutic avenue, as this means that we could reach all the tissues in the body while limiting the duration of exposure to the molecule, thereby reducing possible side effects.

“DAP could represent the first molecule capable of providing therapeutic benefit to patients with cystic fibrosis linked to a nonsense mutation and, more broadly, to patients with a genetic disease linked to a nonsense mutation,” explains Lejeune.

These results pave the way for a potential clinical trial in the coming years to test the efficacy of the molecule in patients. Before this, the goal is to develop the best possible formulation for the drug and to carry out toxicity tests to ensure its safety in humans. In the shorter term, the teams also want to test DAP in models of other rare genetic diseases, particularly Duchenne muscular dystrophy and Rett’s syndrome, for which over 60% of patients are affected by nonsense mutations.

[1] Cancer Heterogeneity, Plasticity and Resistance to Therapies laboratory at the ONCOLille institute

[2]The following research units also contributed to these findings: Communication Molecules and Adaptation of Micro-organisms (CNRS/MNHN), Biometrics and Evolutional Biology Laboratory (CNRS/Université Claude Bernard Lyon 1/VetAgro Sup), Lille Platforms in Biology and Health (PLBS) (CNRS/University Hospital Lille/Inserm/Institut Pasteur Lille/Université Lille), Strasbourg Platform for Integrative Biological Chemistry (CNRS/Université de Strasbourg).

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