Cystic Fibrosis Gene Therapy in the UK and Elsewhere

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.

Cystic Fibrosis: The Dawn of a New Therapeutic Era

“…These treatments should be effective irrespective of CFTR mutation. After the discovery of the CFTR gene in 1989, numerous gene therapy clinical trials have been performed, with minimal direct clinical benefit established (42). However, rather than emphasizing clinical end points, these early studies were performed primarily to illustrate the clinical safety and proof of concept for gene therapy/editing techniques.…”

Nanocomplexes for gene therapy of respiratory diseases: Targeting and overcoming the mucus barrier

“…Concerning the airways, many studies have shown that PEI can promote gene transfer in vivo with an efficiency corresponding up to 5% of pulmonary cells, when administered intravenously [24]. This percentage of positively transfected cells seems to be in the lower range needed to obtain the therapeutic effect, at least for what is concerning cystic fibrosis gene therapy [25].…”

Cystic Fibrosis Gene Therapy – Not Low-hanging Fruit

“…Academia and industry had assumed that the lung would be an easy, non-invasive target, overlooking the fact that potent extra-and intra-cellular barriers interfere with gene transfer into airway epithelial cells. 1 The realisation that CF gene therapy is not 'low-hanging fruit' caused interest to wane and many academics and industry to chase easier disease targets. After the turn of the century, CF gene therapy was pursued by only a small, but highly motivated, number of groups.…”

“…[2][3][4] To date, approximately 27 CF gene therapy trials involving ~600 patients have been conducted. 1 All but two were single-dose phase I/IIa safety studies, which also included assessment of molecular endpoints (measurement of vector-specific mRNA and CFTR-mediated ion transport).…”

“…1 The research community has not yet reached a consensus for adeno-associated vectors (AAV), which is the current vector of choice for a range of eye disorders and haemophilia, for example. [5][6] However, in the context of lung gene transfer, we have not seen any convincing evidence that AAV can be re-administered without loss of efficacy and, therefore, currently question the further development of this vector for CF gene therapy.…”