Margarida D Amaral, BioISI – Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Portugal
Cystic fibrosis (CF) is a life-shortening condition caused by many different mutations in the CF gene which then originate a faulty CFTR protein. As a result of those mutations, CFTR no longer controls the transport of chloride and bicarbonate ions across cell membranes.
Indeed, each person with CF has two CFTR gene mutations (one inherited from the father and another from the mother) out of the 2,104 variants so far reported. Because CFTR indirectly regulates water, the mucus lining the person’s airways becomes thicker and the lining of the lungs becomes dehydrated.
Mucus forms a thin layer of liquid that traps, kills and helps sweep away debris and bugs from the surface of the lungs. However, since the mucus in people with CF has less water in it, it becomes very thick and highly sticky and because bicarbonate regulates pH (the acid/alkali balance) of the CF mucus is also more acidic.
These changes result in the increased susceptibility to severe lung infections and obstruction of airways that characterize this disease, making breathing harder.
New drugs are approved to correct a few of these mutations (1). Yet, there is still no similar curative therapy for around 20% of people with CF, namely those who have ultra-rare mutations, some occurring only in less than 5 families worldwide.
As these individuals do not benefit from the newly approved therapies, if no dedicated therapeutic strategy is developed, they risk being left behind.
Bringing novel medicines to individuals with “orphan” CFTR mutations
Our lab is committed to translating scientific innovation from fundamental research to the clinic, not only to achieve more accurate diagnosis and prognosis of CF (in particular for the atypical forms of the disease, which pose diagnostic dilemmas) but also to match the right drug to individuals with ultra-rare (“orphan”) mutations so that they also benefit from the most recent highly effective drugs.
However, research in our lab also focusses on basic aspects of CF, namely understanding the mechanisms that cause the disease and designing innovative ways of treating the disrupted pathways.
One important ongoing venture is HIT-CF, a European Union-funded research project which aims to provide better treatment and better lives for people with CF and rare mutations.
HIT-CF comprises two parts. The first one is carried out in the lab and during this phase, drug candidates of several companies are tested on around 500 patient-derived mini-intestines (called “organoids”). Secondly, based on the effect detected in the organoids, a smaller group of patients is selected to enrol in clinical trials with the drug candidate that has shown best efficacy in his/her own organoids.
The first (lab) phase of the project is now complete and the clinical trials are expected to start by the end of 2021. This is a real personalized medicine approach which allows testing multiple drugs without any “clinical burden” for the patient who will only test the most efficacious one and thus the one most likely to be highly effective on them.
Identifying ways to bypass the faulty CFTR protein
Another important multi-centric project that our lab is involved with is funded by the CF Trust (UK). This one is looking for strategies which bypass CFTR, relying on the activation of other (“alternative”) channels/transporters to compensate for the absence of functional CFTR, namely those already present in our airways, but in a relatively “silent” state.
This approach will help improve CF lung disease for everyone with CF, independent of the respective CFTR mutations, thus being a real one-size-fits-all approach.
In the scope of this project, we have already identified several genes and compounds that modulate “alternative” channels. Some increase the number of these “alternative” channels present at the surface of airway cells and some enhance their function.
Moreover, some of the identified compounds are either drugs already approved for clinical use in other diseases (by US or European agencies) or natural compounds that exist in our body (i.e., compounds that result from the body breaking down a substance).
During the past year and a half of the COVID-19 pandemic, people at our lab had to face several constraints and limitations. However, we felt that we could not bring our research to a complete halt, as there are individuals out there for whom the disease clock is ticking and who expect therapeutic solution from our work that will give them long-awaited quality of life.
So, the coronavirus crisis did not stop our activities! People continued to go to the lab, with all precautions, and regular online meetings are held to discuss data, coordinate the work and plan the next steps in the experiments. In fact, I can say, 2020 was one of the most productive year of my career (if not the most productive) with 21 papers accepted for publication.
To hear more about these and other aspects of our research, register by 26 August for The Physiological Society’s conference called New Roles for Ion Channels and Transporters in Health and Disease.
Notes
- Dates of EMA approval were: ivacaftor (Kalydeko®) – 23 July 2012; lumacaftor + ivacaftor (Orkambi®) – 15 November de 2015; tezacaftor+ ivacaftor (Symkevi®) – 31 October 2018; and tezacaftor + elexacaftor + ivacaftor (Kaftrio®)- 21 August 2020.