Editors' ChoiceCystic Fibrosis

Inspirational genes

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Science Translational Medicine  22 Jul 2015:
Vol. 7, Issue 297, pp. 297ec122
DOI: 10.1126/scitranslmed.aac8564

Cystic fibrosis is a hereditary disease that affects the sweat glands, lungs, digestive system, and male fertility. This condition is caused by a mutation in the CFTR gene and has been a target for gene therapy since 1989.

Alton et al. investigated the clinical efficacy of nonviral CFTR gene therapy in cystic fibrosis patients. They conducted a randomized, double-blind, placebo-controlled trial in cystic fibrosis patients 12 years or older with any combination of CFTR mutations and a forced expiratory volume in 1 second (FEV1) of 50 to 90% predicted. Study participants received nebulized treatments at 28-day intervals (+/- 5 days) for 12 months, with 5 mL of either 0.9% saline or pGM169/GL67A gene-liposome complex. The authors also performed a mechanistic substudy, which included a “nasal group” of participants who received 2 mL of placebo or pGM169/GL67A divided between nasal cavities via a nasal spray device at the time of each nebulized dose. The primary outcome was relative change in percentage predicted FEV1.

Over a year, 140 individuals were randomized to receive either placebo (n = 62) or pGM169/GL67A (n = 78), but 116 individuals were in the per-protocol population, defined as patients who received at least 9 doses of the treatment. Treatment with pGM169/GL67A was shown to have a mild clinical but statistically significant effect on FEV1 at the 12-month follow-up visit. The group treated with pGM169/GL67A was observed to have stabilization of FEV1, whereas a decline in FEV1 was noted in the placebo group. Persons with more severe disease (lower baseline FEV1) were noted to have the best response to therapy. The observations were independent of sex, age, or detection of homozygosity for the most common CFTR mutation. In addition, there were no clinically significant adverse events attributable to treatment with pGM169/GL67A. Because of the small sample size, the investigators were unable to assess infective exacerbations of cystic fibrosis.

This study is the first to demonstrate that nonviral gene therapy can improve lung function in cystic fibrosis patients. Additional studies are needed to determine the optimum dose, dosing interval, and selection of appropriate patients for this therapy. Nevertheless, this study will likely accelerate trials investigating new vectors for gene transfer.

E. W. F. W. 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. Lancet Respir. Med. 10.1016/S2213-2600(15)00245-3 (2015). [Full Text]

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