Gene Therapy for Cystic Fibrosis Improves Lung Function

Ricki Lewis, PhD

July 02, 2015

Monthly administration of liposome-delivered gene therapy for cystic fibrosis (CF) improved forced expiratory volume (FEV) in a randomized, double-blinded, placebo-controlled phase 2b clinical trial.

Researchers reported the results of the trial in an article published online July 3 in the Lancet Respiratory Medicine.

Transfer of wild-type CFTR genes using viral vectors has been disappointing, because the airway epithelium is specialized to ward off viral infection and cells turn over frequently. Therefore, the UK Cystic Fibrosis Gene Therapy Consortium has tested plasmid DNA-liposome complexes delivered frequently in several phase 1 and 2a clinical trials. The current trial assessed efficacy of that approach.

The primary endpoint was relative change in percentage predicted FEV in 1 second (FEV1). Participants were older than 12 years, had a FEV1 of 50% to 90%, and had any CF genotype. Secondary endpoints were completion of the Cystic Fibrosis Questionnaire-Revised score, computed tomography scans, and additional lung function tests.

Patients received the gene–liposome complex or saline placebo by nebulizer every 28 days for a year at 18 facilities in the United Kingdom. They continued standard treatments except for DNase for 24 hours before and after treatment. Subgroups also received the treatment or placebo in a nasal spray or underwent bronchoscopy before the first dose and after the final dose.

At the 12-month follow-up, investigators found "a significant, albeit modest, treatment effect" among the 62 treated patients vs the 54 patients in the placebo group (3.7%; 95% confidence interval [CI], 0.1 - 7.3; P = .046).

However, treatment effect among patients with more severe disease was 6.4% (95% CI, 0.8 - 12.1), and among those with less severe disease, it was 0.2% (95% CI, −4.6 to 4.9), suggesting a larger benefit among more severely affected individuals.

Lung function stabilized in the treatment group, yet declined in the placebo group. The groups did not differ in terms of age, sex, mutation type, Pseudomonas colonization, concurrent drug use, whether or not disease was predominantly in the smaller or larger diameter airways, or treatment-associated adverse effects.

Bronchoscopy revealed vector-specific DNA in 12 of the 14 treated patients who completed the study, but in none of the control patients. Similarly, DNA from the gene therapy was found in the nasal delivery subgroup, but not in those given saline nasal spray.

The researchers caution that although the study was powered to detect clinically relevant pulmonary function changes, it found stabilization, rather than improvement, and not in every treated patient. A limitation of the study may have been nonspecific effects, because the control group received saline and not empty vectors.

Another limitation may be the targeted nature of gene therapy. CF is a complex disorder, with manifestations beyond the lungs. "It seems unlikely that this therapy will impact nonrespiratory manifestations of CF, given the delivery mechanism. However, since most mortality in CF is secondary to respiratory symptoms, this is the most important organ system to target," Alix Ashare, MD, PhD, assistant professor of medicine and anesthesiology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, told Medscape Medical News.

The researchers term the trial "groundwork" and call for stronger vectors that would improve efficacy and the consistency of response.

Fei Sun, MD, PhD, assistant professor of physiology at Wayne State University, Detroit, Michigan, said the results were "promising, because it's the first gene therapy trial for CF to show clinical improvement." However, he added, the change in percentage predicted FEV1 with ivacaftor (Kalydeco, Vertex) is "much more dramatic."

Dr Ashare pointed out that gene therapy may find its niche for CF, despite the success of protein-refolding drugs. "While correctors and potentiators need to be genotype-specific, gene therapy has the potential to be efficacious for all genotypes."

Dr Sun and Dr Ashare were not involved in the study.

A majority of the coauthors report support from Genzyme. Nine coauthors have patents related to the work. The commentators have disclosed no relevant financial relationships.

Lancet Resp Med. Published online July 3, 2015.

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