Bypassing CFTR: An Alternative Approach to Treating Cystic Fibrosis
Author: Ivana Mišová, PhD.
Published at: 01/22/2020
Treatment of cystic fibrosis has come a long way. With the approval of Trikafta in 2019, about 90 % of CF patients are now eligible for some of the CFTR modulators. While that is an enormous success, let us not forget about the rest. Even though many other CFTR modulators are currently being developed, no matter how effective they might be, some people with specific CF mutations will be unable to benefit from them.
Mutations in CFTR cause various problems in CFTR function. When CFTR does not function properly as a channel for chloride ions, it leads to the formation of thick, sticky mucus typical for CF. As severe complications of CF are tightly connected with lung disease, the main focus of modulator therapy is to improve mucus clearance from the lungs. CFTR modulators can help the defective CFTR protein to obtain the correct structure, get to the appropriate place and work as the ion channel. This leads to rehydration of the mucus and facilitates mucociliary clearance. However, some CFTR mutations are so severe (class I mutations) that there is simply no CFTR protein to be helped by the modulators. When the usual approach to treatment is not working, we have to look elsewhere.
One way to fix this situation is to deliver the proper CFTR protein via genetic therapy. This is a path that is now being explored, but it has its own challenges (see Genetic therapy of cystic fibrosis). An alternative possibility is to bypass CFTR altogether and substitute the function of CFTR by another protein. To do this, we need another protein that is present in the right type of cells and transports the same type of ions.
This is where the TMEM16A protein comes in. As a calcium-activated chloride channel in the airway epithelial cells, TMEM16A is a promising candidate for substituting the role of CFTR. Due to the mechanism of this particular channel, simply activating it with calcium ions would ultimately slow mucus transport. Rather than activating the channel, scientists focused on enhancing ion secretion from TMEM16A. This research led to the discovery of a potentiator named ETX001. Recently published tests on human airway epithelial cells from CF patients showed that ETX001 increased fluid secretion by potentiating TMEM16A. This potentiator was also tested in vivo, where it could enhance mucus clearance in sheep airways whether CFTR was functional or not1.
These findings open up an exciting opportunity for CF treatment. As TMEM16A potentiating is independent of CFTR function, it could present a treatment possibility for all CF patients, regardless of their CFTR mutation. Alternative approaches to treating CF give hope to those patients that are not eligible for, or cannot tolerate the available modulators. For the CF community, 2020 started strong.
1 - H. L. Danahay et al., “TMEM16A Potentiation: A Novel Therapeutic Approach for the Treatment of Cystic Fibrosis,” Am. J. Respir. Crit. Care Med., p. rccm.201908-1641OC, Jan. 2020.