A mutation-agnostic therapy for cystic fibrosis

Cystic fibrosis (CF) is a genetic disorder caused by defects in a protein involved in the traffic of salt in and out of cells. TAT-CF’s new therapeutic approach for this condition, which notably causes severe damage to the lungs and digestive system, could be a game changer.

Scientists across Europe are hard at work trying to deliver the 200 new therapies for rare diseases awaited by the EU before 2020. Saying that CF is one of the biggest challenges facing them would be an understatement: Whilst mutations and resulting malfunction of the CFTR protein have long been identified as the cause of the disease, the number of possible mutations – over 2 000 – means that therapeutic approaches must be mutation-specific and can only benefit patients sharing the same functional defect. That is, unless the field can witness a complete paradigm change.

Researchers funded under TAT-CF (Novel therapeutic approaches for the treatment of cystic fibrosis based on small molecule transmembrane anion transporters) project have been intending to rock the boat since 2016. Instead of investigating new mutation-specific treatments, they have been working on molecules able to mimic CFTR function, potentially enabling mutation-agnostic therapies that can benefit all CF patients. “The current results in clinical trials for combinations of potentiators and correctors are very encouraging. But the downside is that these developments cannot provide therapeutic options to all CF patients. In particular, there are several classes of mutations, such as nonsense mutations, resulting in no CFTR being produced. In this case, pharmacological modulation or rescue of CFTR activity is completely ineffective,” Dr Roberto Quesada explains.

“More than 200 compounds were evaluated by the different partners involved in our consortium,” says Dr Quesada, coordinator of the project. “We had to find the right balance between molecular properties, transport activity and toxicity of the candidates to select the appropriate leads for our project.”

The compounds have been tested on cell lines obtained from patients with different mutations and through gene editing. As Dr Quesada points out, “this means that we have been able to test them in cells and organoids having different functional defects as well as models in which CFTR expression was completely absent.”

Using synthetic epithelium derived from primary human bronchial epithelial cells, the team could show that the compounds they selected could bring CF epithelia function to normal values in terms of fluid reabsorption and mucus viscosity – two key parameters in the pathophysiology of CF patients.

Besides, the compounds were tested in combination with approved CF drugs and observed additive effects, which could also be envisaged to be a promising approach for the treatment of different mutations.

The next step for TAT-CF partners is in vivo research to confirm the obtained results. For testing on relevant animal models, the team has decided to focus on pulmonary disease as the main cause of morbidity and mortality of CF patients. They have already developed nanoformulations suitable for pulmonary delivery and performed ADME-Tox studies in mice models. “Now, we would need to confirm their safety and efficacy in an appropriate animal model for respiratory tract disease before proceeding with clinical trials in humans,” Dr Quesada explains.

All in all, TAT-CF’s research paves the way to new therapies bypassing CFTR function using synthetic molecules. A patent application has already been filed, and the consortium is currently looking for new (public or private) sources of funding.