Cellular screen identifies therapies that may help boost CFTR function

PDE4 inhibitors may be effective for CF patients ineligible for current therapies

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A class of therapies called PDE4 inhibitors, which are approved to manage certain inflammatory diseases, may help boost the functionality of the protein whose defect causes cystic fibrosis (CF), according to a new study.

Results also suggest that some available CF treatments may be effective in a broader array of patients than are currently covered by existing approvals.

The study, “FDA-approved drug screening in patient-derived organoids demonstrates potential of drug repurposing for rare cystic fibrosis genotypes,” which was published in the Journal of Cystic Fibrosis.

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Need for treatment of CF patients with mutations not amenable to modulators

Cystic fibrosis is caused by mutations in the gene that provides instructions for making the CFTR protein, which normally helps to regulate the movement of chloride ions, a type of negatively charged salt particle, in and out of cells. As a result of these mutations, the CFTR protein does not function properly, which leads to a thick, sticky mucus that drives most CF symptoms.

Recently, a new class of medications called CFTR modulators have become available. These therapies can help boost the functionality of the defective protein in people with specific disease-causing mutations. CFTR modulators are widely approved for nearly 90% of patients, but many patients do not carry any mutation amenable to modulator treatment. As such, there’s a need to find new therapies that may improve CFTR function, particularly for people who cannot be treated with modulators.

A team of scientists in the Netherlands had previously devised a cellular model that they could use to efficiently screen for molecules that affect CFTR function.

The model involves taking patient cells and growing them into intestinal organoids, which are lab-made cellular structures that mimic the three-dimensional architecture of cells in human tissue. When these organoids are treated with a CFTR-activating chemical, the organoid swells up as fluid flows into them. But, if the protein’s function is impaired, there’s little or no swelling.

This model “is advantageous when the goal is to characterize compounds that specifically enhance CFTR-mediated fluid secretion,” the researchers wrote.

These results underline the relevance of continuing to screen non-eligible [mutations] with CFTR modulators and to potentially expand the label of these compounds.

Model organoids created and used to screen 1,400 compounds approved in US

In this study, the researchers created model organoids derived from 76 people with CF and covering 58 different sets of CF-causing mutations, including many that are not currently covered for modulator treatment. These organoids were used to screen 1,400 compounds that are already approved by the U.S. Food and Drug Administration to treat at least one health condition.

From this broad screen, the team identified three classes of medications that appeared to boost CFTR function. One class, tyrosine kinase inhibitors, are generally used for cancer and can cause severe safety issues, so the researchers said these probably aren’t suitable for routine use in CF.

Another class was CFTR modulators, which was expected since these therapies are designed to increase the protein’s functionality. However, the researchers noted that CFTR modulator treatment showed a CFTR-enhancing effect in cells from patients with mutations that are not currently eligible for these therapies.

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In particular, the modulator Kalydeco (ivacaftor) appeared to increase CFTR function in cells from patients with combinations of mutations referred to as N1303K/Q1012P, 4382delA/2043delG, and R334W/R334W, which aren’t currently approved for this therapy.

“These results underline the relevance of continuing to screen non-eligible [mutations] with CFTR modulators and to potentially expand the label of these compounds,” the researchers wrote.

The third class of medication picked up by the screen was PDE4 inhibitors. In particular, the PDE4 inhibitor roflumilast, which currently is approved to treat chronic obstructive pulmonary disease, appeared to boost CFTR function in many of the tested organoids.

“As next step, we believe it is of great interest to conduct clinical studies to test the effects of roflumilast and existing CFTR modulators for those patients who could benefit from either or both based on preclinical data described in this study,” the team concluded.