Emerging gene therapies for cystic fibrosis

ABSTRACT

Introduction: Cystic fibrosis (CF) remains a life-threatening genetic disease, with few clinically effective treatment options. Gene therapy and gene editing strategies offer the potential for a one-time CF cure, irrespective of the CFTR mutation class.

Areas covered: We review emerging gene therapies and gene delivery strategies for the treatment of CF particularly viral and non-viral approaches with potential to treat CF.

Expert opinion: It was initially anticipated that the challenge of developing a gene therapy for CF lung disease would be met relatively easily. Following early proof-of-concept clinical studies, CF gene therapy has entered a new era with innovative vector designs, approaches to subvert the humoral immune system and increase gene delivery and gene correction efficiencies. Developments include integrating adenoviral vectors, rapamycin-loaded nanoparticles, and lung-tropic lentiviral vectors. The characterization of novel cell types in the lung epithelium, including pulmonary ionocytes, may also encourage cell type-specific targeting for CF correction. We anticipate preclinical studies to further validate these strategies, which should pave the way for clinical trials. We also expect gene editing efficiencies to improve to clinically translatable levels, given advancements in viral and non-viral vectors. Overall, gene delivery technologies look more convincing in producing an effective CF gene therapy.

Trial registration: ClinicalTrials.gov identifier: NCT01621867.

Trial registration: ClinicalTrials.gov identifier: NCT02564354.

Trial registration: ClinicalTrials.gov identifier: NCT02532764.

Trial registration: ClinicalTrials.gov identifier: NCT03375047.

Trial registration: ClinicalTrials.gov identifier: NCT03288493.

Trial registration: ClinicalTrials.gov identifier: NCT03140969.

Trial registration: ClinicalTrials.gov identifier: NCT03605069.

Trial registration: ClinicalTrials.gov identifier: NCT03780257.

Trial registration: ClinicalTrials.gov identifier: NCT02939820.

Trial registration: ClinicalTrials.gov identifier: NCT03399448.

KEYWORDS:

• CFTR
• Cystic Fibrosis
• gene delivery gene therapy
• genome editing
• non-viral vectors
• viral vectors

Article highlights

• Viral vectors have been improved and are being re-evaluated for CF gene therapy applications.

• Rational design of AAVs has improved vector gene transfer efficiencies and/or evasion of the immune response, in comparison with their prototypical counterparts.

• Hybrid piggyBac/Ad vector systems permit persistent CFTR gene transfer and correction in vitro, but require longitudinal studies to examine benefits in vivo.

• First-in-human clinical trials using recombinant lentiviral-based vectors pseudotyped for the lung are highly anticipated.

• Pulmonary ionocytes represent a newly identified cell type of airway epithelia, and may be a significant source of CFTR activity, highlighting it as a target cell for gene therapy.

• Gene editing, including using CRISPR/Cas9, for CF correction is beginning to establish itself as a novel class of therapeutics

Declaration of interest

Deborah R. Gill and Stephen C. Hyde hold patents in F/HN lentiviral vector technology. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewers Disclosure

A reviewer on this manuscript has disclosed funding by the cystic fibrosis trust, is a shareholder in Ryboquin and has received consultancy fees from Glaxo SmithKline (GSK), Sanofi and Ryboquin; they also have shares in Nanogenics Ltd. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This review has been supported by the Wellcome Trust (Stephen Hyde & Deborah Gill) and by the Department of Health and Wellcome Trust through the Health Innovation Challenge (HIC) Fund (Kamran Miah, Stephen Hyde & Deborah Gill).