Promising breakthrough in Cystic Fibrosis research: Nebulization of CFTR gene therapy

For the first time, a non-viral gene therapy in a phase 2 trial has been demonstrated to be advantageous to lung function in people afflicted with cystic fibrosis (1). Normally, people with cystic fibrosis have one or more mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. These mutations damage the lining of the lungs and impair mucus transportation, leaving patients vulnerable to frequent infections that eventually lead to death in 90% of people with cystic fibrosis (2).

In a groundbreaking study, researchers with the U.K. Cystic Fibrosis Gene Therapy Consortium used an inhaled plasmid gene-liposome complex, pGM169/GL67A, to deliver a working copy of CFTR to the participants in the trial. Previous studies have tried to use viruses, such as adenoviruses and retroviruses, to transfer the CFTR gene. These viral approaches have not been successful, in part because they induced the participants’ immune response.

This study occurred over the span of a year and involved 136 patients over the age of 12 who had various CFTR mutations (1). Every 28 days, participants received 5mL of either nebulized 0.9% saline or pGM169/GL67A. Researchers measured the effectiveness of the treatment by comparing the relative change in percent predicted forced expiratory volume (FEV₁).

After a year of treatment, participants who received the pGM169/GL67A had a 3.7% larger FEV₁ than the placebo group (1). However, the difference between the placebo and experimental groups’ FEV₁ was largely due to the placebo group’s decline in FEV₁, meaning that the GM169/GL67A likely stabilized, rather than improved, respiratory function (1). Importantly, the researchers did not find any adverse side effects due to the GM169/GL67A treatment (1).

Patients with more severe cases of cystic fibrosis, those who had the lowest predicted FEV₁ before treatment, benefited the most from the GM169/GL67A. They improved their FEV₁ by 6.4% compared to patients with less severe cases who improved their FEV₁ by 0.2% (1).

The researchers hypothesize that the patients with initially more severe cases of cystic fibrosis had larger gains in FEV₁ because they were better able to absorb the GM169/GL67A (1). In comparison to patients with milder symptoms, patients with severe cases had more obstruction in their small airways, resulting in more GM169/GL67A deposits in their large airways (1). Additionally, these patients with severe cases of cystic fibrosis have more damaged lung tissue, which has a higher mitotic rate than healthy tissue. During mitosis, the nuclear membrane temporarily dissolves, which may allow for better absorption of the plasmid DNA into the nucleus.

The researchers will continue to observe whether GM169/GL67A group’s relatively stabilized respiratory function is maintained over time (1). They noted that, while the treatment’s effect on patients was significant, it was still “modest” (1). The researchers hope continued research will improve their treatment’s “efficacy and consistency of response” (1). They also hope that their study will “encourage the rapid introduction of more potent gene transfer vectors into early phase trials,” now that they have demonstrated a safe form of repeated, non-viral CFTR gene therapy (1).

References:

1. Eric Alton et al. Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial. The Lancet Respiratory Medicine, 2015 DOI:1016/S2213-2600(15)00245-3
2. The Lancet. (2015, July 3). First trial of gene therapy for cystic fibrosis to show beneficial effect on lung function. ScienceDaily. Retrieved July 11, 2015 from www.sciencedaily.com/releases/2015/07/150703072624.htm