CF gene therapy restores rat CFTR function as well as modulators
Rat lung cells respond similarly to therapies, study finds
Gene therapy was found to work as well as a combination of the three CFTR modulators in Trikafta to restore the function to the CFTR protein, which is faulty in cystic fibrosis (CF), with the potential to work for all patients, regardless of their disease-causing mutation.
That’s according to a study carried out in lung cells from a rat model of CF.
The study, “Lentiviral vector gene therapy and CFTR modulators show comparable effectiveness in cystic fibrosis rat airway models,” was published in the journal Gene Therapy.
CF is caused by mutations in the CFTR gene that result in thick mucus building up in the lungs and other organs in the body, causing a range of symptoms. Current CFTR modulators are designed to correct the faulty protein made from the CFTR gene, but they only work for patients with specific mutations.
A team of researchers in Australia is exploring an approach that involves adding a healthy copy of the CFTR gene to cells in the airways, so that they can make a working version of the protein on their own. “Gene-addition therapy is a promising strategy for tackling CF lung disease and may provide an effective alternative for those without adequate treatment options,” the team wrote. The researchers set out to investigate whether that gene therapy-based approach restores CFTR function in the airways and if it works as well as CFTR modulators.
‘Gold standard’
“As CFTR modulators are now considered the gold standard treatment for most people with CF,” the researchers wrote, “all new therapies will likely need to demonstrate comparable effectiveness in their ability to restore CFTR function.”
They used two rat models of CF in the study: one in which the disease is caused by the common F508del mutation, and the other in which the CFTR gene is inactivated (knockout, or KO), preventing the production of CFTR. Researchers isolated cells from the rats’ tracheas and grew them in the lab to mimic the environment in the airways.
Gene therapy was carried aboard a modified lentivirus, a type of virus that is often used as a delivery vehicle for genetic material. Its effects were compared with those of a combination of elexacaftor, tezacaftor, and ivacaftor, the CFTR modulators found in Trikafta.
Compared with healthy cells, those isolated from animals carrying the F508del mutation had 32% of normal CFTR function, indicating residual activity. Those from KO rats had only 6% of normal CFTR function.
Treating cells carrying the F508del mutation with the triple combination of CFTR modulators increased CFTR function to 59% of normal. Gene therapy restored CFTR function to 68% of normal in cells carrying the F508del mutation, and to 47% in KO cells.
“Gene-addition therapy produces similar levels of CFTR restoration to [elexacaftor, tezacaftor, and ivacaftor], an important finding given that modulator drugs are now the benchmark for which all new CF therapies will be compared,” the researchers wrote. They said their work ““provides further support for the continued development of a gene-addition therapy for CF and offers the possibility to provide a mutation-agonistic treatment for those without modulator therapies.”
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