New Test Could Lead to Effectively Customizing Treatments for CF Patients, Study Contends

A simple new test may help identify which CFTR modulators are more effective for treating individual patients with cystic fibrosis (CF), early results from a pilot study show.

The test finds which compounds are more effective in restoring the beating of patient-derived airway cilia, which are hair-like structures that line the human airways and whose movement is disrupted in patients with CF.

Researchers believe this tool may lead to personalized therapy in CF patients, as well as for other disorders in which cilia movements are disrupted. 

The findings, “Phenotyping ciliary dynamics and coordination in response to CFTR-modulators in Cystic Fibrosis respiratory epithelial cells,” were published recently in the journal Nature Communications, and featured in a news story by Ziba Kashef from Yale University.

The thick mucus that is characteristic of CF obstructs breathing, and disrupts the beating of cilia covering the cells lining our lungs and upper airways.

Cilia normally beat in a rhythmic, sweeping fashion, toward the mouth to help move airway mucus (swallowed or coughed out). This self-clearing mechanism, known as mucociliary clearance, helps keep harmful microbes and irritants away.

As the thick mucus of CF patients accumulates in airway surfaces, it restricts the cilia beatings, and these changes can be observed and quantified in the lab by specialized microscopy techniques.

In the study, researchers at University of Cambridge and Yale School of Medicine, took advantage of the disrupted ciliary movements observed in CF patients to create a test that screens for the most effective therapies in restoring such cilia movements.

If the defect on CF cells is partially corrected by a specific compound, then less thick mucus will be produced, and the cilia will beat at a rhythm closer to how they would on healthy cells.

To observe and quantify these changes with high-resolution, the test combines automatic high-speed video microscopy (multiscale differential dynamic microscopy, multi-DDM) and a new video analysis algorithm model.

In the pilot study, researchers examined the cilia of airway epithelial cells isolated from patients with different CF mutations (F508del on one or both copies of the CFTR gene, which is the gene defective in CF patients), and compared those samples to normal cells.

Researchers measured how the beat frequency and coordination of cilia changed in response to six different CFTR-modulating compounds: the CFTR corrector lumacaftor (VX-809), the FDA-approved CFTR potentiator Kalydeco (ivacaftor), and a combination of both, sold as Orkambi (lumacaftor/ivacaftor); and two other investigational CFTR correctors (C4 and C18), alone or combined. Of note, lumacaftor, Kalydeco, and Orkambi were all developed by Vertex Pharmaceuticals.

The assay was able to quantitatively identify the most efficient compounds to restore cilia beating in each patient.

By identifying which specific modulators best restore ciliary beating, researchers argue that this test could be a fast and efficient way to help predict treatment effectiveness in patients in a personalized way.

That is an important feature, “as patient-to-patient variation is an obstacle to therapeutic intervention and cannot currently be explained by mutation/s in the CFTR gene alone” the researchers wrote.

The team believes that such an approach may pave the way for personalized medicine, helping to tailor treatments for CF patients.

Also, as problems in cilia dynamics are evident for other diseases, the test is not limited to CF, but also may have applications in other disorders.

Yale University made available a microscopy video record of some of the cilia analyzed in the study. The video can be viewed here.