New Step Toward Gene Cure For Cystic Fibrosis Interview with:
Dragana Vidovic and Marianne Carlon

Laboratory for Molecular Virology and Gene Therapy
KU Leuven, Belgium

Medical Research: What is the background for this study? What are the main findings?

Response: Cystic fibrosis (CF) or mucoviscidosis is a genetic disorder caused by mutations in the CFTR gene which codes for a chloride/bicarbonate channel that regulates fluid secretion across the epithelium in different organs, for instance, the airways and the gastrointestinal tract. In the cells of CF patients, these anion channels are dysfunctional or even absent leading to the formation of sticky mucus. Persistent airway infection is the major clinical manifestation. The symptoms can be treated, but there is no cure for the disorder. Gene therapy holds promise to cure the disease. Previous studies suggested that the treatment is safe, but largely ineffective for Cystic fibrosis patients. However, as gene therapy has recently proven successful for inherited disorders such as haemophilia and congenital blindness, we wanted to re-examine its potential for CF.

Here we developed an improved gene therapy treatment based on inserting the CFTR gene into the genome of a recombinant AAV viral vector (rAAV), which is derived from the relatively innocent AAV virus. We used this vector to “smuggle” a healthy copy of the CFTR gene into the affected cells. We administered rAAV to CF mice via their airways. Most of the mice recovered. In patient-derived intestinal cell cultures or organoids, chloride and fluid transport was restored.

Medical Research: What does the study add to the field?

Response: Development of Cystic fibrosis gene therapy requires a thorough preclinical examination of a candidate vector in relevant cell and animal models before being administered to humans. Here, both in mice with Cystic fibrosis and in mini-guts or intestinal organoids derived from Cystic fibrosis patients, this approach yielded positive results setting the stage for further validation in large animal models which mimic the CF patient situation more faithfully. We believe that our study will revive the interest in CF gene therapy as a promising, mutation-independent approach to ultimately cure Cystic fibrosis.

Medical Research: What should clinicians and patients take away from your report?

Response: We must not give Cystic fibrosis patients false hope. Developing a treatment based on gene therapy will take years of work. For one thing, our study did not involve actual human beings, only mice and patient-derived cell cultures. But gene therapy clearly is a promising candidate for further research towards a cure for cystic fibrosis.

Medical Research: What recommendations do you have for future research as a result of this study?

Response: We still have to examine how long the therapy works. Repeated doses might be necessary to ensure a prolonged therapeutic benefit. Also, our candidate gene therapy product will have to be validated in a larger animal model that develops clear lung pathology as seen in Cystic fibrosis patients to evaluate its potential to prevent or cure lung disease. This would be a crucial step towards the development of a gene-based treatment for Cystic fibrosis.


Dragana Vidović, Marianne S Carlon, Mélanie F. da Cunha, Johanna F Dekkers, Monika I Hollenhorst, Marcel J C Bijvelds, Anabela S Ramalho, Chris Van den Haute, Marc Ferrante, Veerle Baekelandt, Hettie M Janssens, Kris De Boeck, Isabelle Sermet-Gaudelus, Hugo R. de Jonge, Rik Gijsbers, Jeffrey M Beekman, Aleksander Edelman, Zeger Debyser.rAAV-CFTRΔR Rescues the Cystic Fibrosis Phenotype in Human Intestinal Organoids and CF Mice. American Journal of Respiratory and Critical Care Medicine, 2015; DOI: 10.1164/rccm.201505-0914OC

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Dragana Vidovic and Marianne Carlon (2015). New Step Toward Gene Cure For Cystic Fibrosis