Key learning points 

  • Around 2000 mutations that cause cystic fibrosis have been identified 
  • Small molecule drugs called modulators have been developed to tackle specific mutations of cystic fibrosis 
  • Lentiviral pseudotyped vectors may provide effective gene delivery in the human lung 
  • The future of gene therapy for cystic fibrosis relies on innovation to improve efficiency of lung cell targeting and clinical efficacy for further progress


Cystic fibrosis (CF) is a progressive, life-threatening, genetic disease affecting multiple organs, but in particular the lungs which rapidly deteriorate due to chronic infection and inflammation. Conventional treatments aim to manage these challenges with anti-inflammatory drugs, antibiotics to control airway infections, and daily physiotherapy to remove mucus.1 

The discovery of the CF gene in 1989 ushered in the potential to develop a gene therapy to treat this genetic disease.2 Understanding the genetic basis of CF, and the effects of some 2000 mutations that have been identified, has also facilitated the development of small molecule drugs (modulators) to tackle specific mutations with significant patient benefit.3,4 The modulators act inside the cell to aid the processing of the mutant CFTR protein as it moves towards the cell membrane (‘correctors’), or to potentiate the activity of the mutant CFTR protein once it is inserted in the membrane (‘potentiators’).4 However, many CF individuals remain without effective treatment options and gene therapy could replace or repair the defective gene, providing a one-for-all treatment irrespective of mutation type.5

Gene therapy 

Multiple early gene therapy clinical trials were designed to test the feasibility of gene therapy for CF lung disease, but failed to offer clinical benefit in CF patients; more promising results have since been obtained. Aerosol delivery of a synthetic gene therapy, composed of plasmid DNA complexed with cationic liposomes, was administered to CF patients every month for a year and showed a stabilisation of lung function decline compared with patients receiving a placebo, irrespective of their mutation type.6 Although the observed clinical benefits were modest, this was the first time that a sustained improvement in lung function was possible with gene therapy, demonstrating that this type of approach was feasible. 


These encouraging results have re-kindled innovation in the development of more efficient lung gene delivery systems (vectors) that will be needed to fully realise clinical benefit. Rather than using synthetic vectors, increased efficiency and efficacy is offered by the use of modified viruses. An important focus is to develop viral vectors that are efficient for entering (transducing) lung cells. In the case of adeno-associated virus (AAV) and lentiviral vectors, this can be achieved by selecting, engineering, or ‘evolving’ targeting proteins on the surface of the viral vector. In clinical trials of CF gene therapy using recombinant AAV, the results were disappointing with the commonly-used serotype 2.7 Human-derived tissues can be used to identify new AAV serotypes that might be more relevant, such as the chimera of the very common AAV serotype 2 and human bocavirus, which can efficiently transduce polarised human airway epithelia cell lines and organoids.8 

Lentiviral vectors, based on immunodeficiency viruses, can integrate into the genome offering long-term gene expression. The development of new lentiviral pseudotypes, via addition of glycoproteins such as gp64 from Baculovirus or the F/HN coat proteins from Sendai virus, may offer more effective transduction in the human lung.9,10 These vectors appear efficient in animal models and show promise in evading the immune system to allow successful repeated administration; we await the evaluation of these pseudotyped lentiviral vectors in the clinic.11,12

Gene editing The gene therapy approach has expanded to also include gene editing, with the potential to permanently correct the genetic mutations underlying disease. Gene editing is mediated by nucleases, and in particular the commonly used gene editing system known as CRISPR/Cas9 (clustered regulatory interspaced short palindromic repeats).13 This technology is routinely employed in a laboratory setting, and increasingly in animal disease models, but gene editing faces many challenges before being declared sufficiently reliable as a new therapeutic in clinical trials. Since proof-of-concept has already been demonstrated for CF gene therapy, innovation to improve efficiency of lung cell targeting and clinical efficacy is the key focus for further progress.

Professor Deborah Gill, Co-Director of Gene Medicine Research Group, John Radcliffe Hospital, Oxford

This project was initiated and funded by Teva Respiratory. Teva have had no influence over content. Topics and content have been selected and written by independent experts.

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