Roadmap for an early gene therapy for cystic fibrosis airway disease

Abstract

Gene therapy provides a mutation-independent approach to treat or even cure CF airway disease. To develop a clinical candidate for CF gene therapy, a thorough examination of preclinical efficacy in relevant cell and animal models is a prerequisite. For a long time, the CF field was struggling with a lack of appropriate animal models for CF airway pathology. Since 2008, many different and complementary animal models have been generated that develop hallmarks of CF airway disease, including the CF pig, ferret, and rat. With this, a new era has arisen that allows investigating the efficacy of gene therapy beyond molecular and electrophysiological end-points. Successful gene therapy most likely requires an appropriate time window. CF lung pathology progresses with age and therefore an early treatment would be beneficial to prevent irreversible damage. In that regard, newborn screening programs and prenatal diagnosis already provide a basis to facilitate future preventive gene-based treatment. If successful, gene therapy for CF airway disease would markedly reduce the treatment burden and improve life quality and life expectancy of CF patients.

Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing

“…In search for a cure for CF, several gene therapy approaches have been explored 5 , mostly based on CFTR cDNA gene addition through viral or non-viral vectors 6,7 . Despite promising results obtained in the respiratory tract of animal models 8–10 and advancements in gene therapy clinical trials 11–14 , curative goals were hampered mainly by low expression levels of the delivered CFTR .…”

Innovative Therapeutic Strategies for Cystic Fibrosis: Moving Forward to CRISPR Technique

“…The greatest obstacle to clinical success is the efficacy of gene delivery ( Carlon et al, 2017 ). There are many approaches to improve this aspect, but viral and non-viral vectors are the most used vectors to carry nucleic acids into the cells.…”

“…Recently, the UK CF Gene Therapy Consortium (GTC) has completed a double-blinded, placebo-controlled multi-dose phase IIb trial with 12 years or older age patients with moderate or mild lung disease. This trial has demonstrated that gene delivery was well-tolerated but benefit of liposome delivery was modest ( Carlon et al, 2017 ).…”

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“…It is unclear whether appropriate research ethics approvals and parental consent were available. We do hope that this reckless “Wild West” behaviour will not put a brake on appropriately done gene therapy research, as this form of therapy may bring significant progress, especially in the field of fertility treatment, hematologic disorders (thalassemia and sickle cell disease) as well as for other genetic conditions, including cystic fibrosis …”