Topical cystic fibrosis transmembrane conductance regulator gene replacement for cystic fibrosis-related lung disease

  • Review
  • Intervention

Authors

  • Tim WR Lee,

    Corresponding author
    1. Children's Day Hospital, St James's University Hospital, Leeds Regional Paediatric Cystic Fibrosis Centre, Leeds, UK
    • Tim WR Lee, Leeds Regional Paediatric Cystic Fibrosis Centre, Children's Day Hospital, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK. timlee@doctors.org.uk.

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  • Kevin W Southern

    1. University of Liverpool, Institute of Child Health, Liverpool, Merseyside, UK
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Abstract

Background

Cystic fibrosis is caused by a defective gene encoding a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), and is characterised by chronic lung infection resulting in inflammation and progressive lung damage that results in a reduced life expectancy.

Objectives

To determine whether topical CFTR gene replacement therapy to the lungs in people with cystic fibrosis is associated with improvements in clinical outcomes, and to assess any adverse effects.

Search methods

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings.

Date of most recent search: 19 July 2012.

An additional search of the National Institutes for Health (NIH) Genetic Modification Clinical Research Information System (GeMCRIS) was also performed for the years 1992 to 2012.

Date of most recent search: 25 July 2012.

Selection criteria

Randomised controlled trials comparing topical CFTR gene delivery to the lung, using either viral or non-viral delivery systems, with placebo or an alternative delivery system in people with confirmed cystic fibrosis.

Data collection and analysis

The authors independently extracted data and assessed study quality. Authors of included studies were contacted and asked for any available additional data. Meta-analysis was limited due to differing study designs.

Main results

Three randomised controlled trials met the inclusion criteria for this review, involving a total of 155 participants. Fourteen studies were excluded. The included studies differed in terms of CFTR gene replacement agent and study design, which limited the meta-analysis.

Although the first Moss study reported a significant improvement in respiratory function (forced expiratory volume at one second) 30 days after participants had received their first dose of gene therapy agent, this finding was not confirmed in their larger second study or in our meta-analysis.

In participants who received the CFTR gene transfer agents in the Alton study, "influenza-like" symptoms were found (risk ratio 7.00 (95% confidence interval 1.10 to 44.61)). There were no other significant increases in adverse events in any of the studies.

Alton measured ion transport in the lower airways and demonstrated significant changes toward normal values in the participants who received gene transfer agents (P < 0.0001), mean difference 6.86 (95% CI of 3.77 to 9.95). In these participants there was also evidence of increased salt transport in cells obtained by brushing the lower airway. These outcomes, whilst important, are not of direct clinical relevance.

Authors' conclusions

There is currently no evidence to support the use of CFTR gene transfer reagents as a treatment for lung disease in people with cystic fibrosis. Future studies need to investigate clinically important outcome measures.

Plain language summary

Replacing the defective gene is a potential treatment for progressive lung disease in people with cystic fibrosis

In cystic fibrosis the gene encoding a protein called the cystic fibrosis transmembrane conductance regulator (CFTR) is faulty. People with cystic fibrosis suffer from progressive lung infection and damage which reduces life expectancy. Agents for CFTR gene transfer may be an effective treatment as they deliver a correct copy of the CFTR gene to lung cells.

We found three trials with 155 participants to include in this review. The trials compare gene therapy to placebo which is nebulised to the lungs. The trials were of different designs and used different agents. This meant we could not combine them all in a meta-analysis. We found significant changes toward normal ion transport values in the lower airways of people who received gene transfer agents. However, we found no evidence that outcome measures which are clinically relevant to people with cystic fibrosis had improved. In one study "influenza-like" symptoms were significantly more common in people who received CFTR gene transfer agents. We conclude that at the moment there is no evidence to support the use of CFTR gene transfer agents as a treatment for lung disease in people with cystic fibrosis. We recommend that future studies are designed and reported clearly so that their results can be incorporated into a systematic review.