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Cystic Fibrosis Gene Therapy in the UK and Elsewhere
Uta Griesenbach1, Kamila M Pytel1, Eric W F W Alton1
1Department of Gene Therapy and the U.K. Cystic Fibrosis Gene Therapy Consortium, Imperial College, London SW3 6LR, United Kingdom.
Abstract:
The cystic fibrosis transmembrane conductance regulator (CFTR) gene was identified in 1989. This opened the door for the development of cystic fibrosis (CF) gene therapy, which has been actively pursued for the last 20 years. Although 26 clinical trials involving approximately 450 patients have been carried out, the vast majority of these trials were short and included small numbers of patients; they were not designed to assess clinical benefit, but to establish safety and proof-of-concept for gene transfer using molecular end points such as the detection of recombinant mRNA or correction of the ion transport defect. The only currently published trial designed and powered to assess clinical efficacy (defined as improvement in lung function) administered AAV2-CFTR to the lungs of patients with CF. The U.K. Cystic Fibrosis Gene Therapy Consortium completed, in the autumn of 2014, the first nonviral gene therapy trial designed to answer whether repeated nonviral gene transfer (12 doses over 12 months) can lead to clinical benefit. The demonstration that the molecular defect in CFTR can be corrected with small-molecule drugs, and the success of gene therapy in other monogenic diseases, is boosting interest in CF gene therapy. Developments are discussed here.
Insights
Cystic fibrosis (CF) gene therapy research has advanced, with trials focusing on safety and proof-of-concept. Recent studies explore clinical efficacy of gene transfer for CFTR gene defects.
Area of Science:
- Biomedical research
- Gene therapy
- Molecular medicine
Background:
- The cystic fibrosis transmembrane conductance regulator (CFTR) gene was identified in 1989, initiating CF gene therapy development.
- Over 20 years, 26 clinical trials (approx. 450 patients) have primarily assessed safety and proof-of-concept for gene transfer.
- Previous trials used molecular endpoints; few were designed for clinical efficacy, with one published trial using AAV2-CFTR.
Purpose of the Study:
- To review the progress and developments in cystic fibrosis (CF) gene therapy.
- To highlight the shift towards assessing clinical efficacy in CF gene therapy trials.
- To discuss the impact of small-molecule drugs and gene therapy successes in other diseases on CF gene therapy interest.
Main Methods:
- Review of 26 clinical trials in cystic fibrosis (CF) gene therapy.
- Analysis of trial designs focusing on safety, proof-of-concept, and clinical efficacy.
- Inclusion of data from a completed nonviral gene therapy trial (UK CFGT Consortium).
Main Results:
- Most CF gene therapy trials focused on safety and molecular endpoints, not clinical benefit.
- One published trial assessed clinical efficacy using AAV2-CFTR, with lung function as the endpoint.
- A nonviral gene therapy trial demonstrated repeated gene transfer over 12 months.
Conclusions:
- Advancements in CFTR gene therapy are driven by small-molecule drug successes and gene therapy progress in other monogenic diseases.
- There is a growing interest in CF gene therapy, with a focus on achieving clinical benefit.
- Future research directions in CF gene therapy are influenced by past trial outcomes and emerging therapeutic strategies.
