Advanced Gene Therapy Cures Cystic Fibrosis in Culture and Mouse Models

Improvements in gene therapy technology enabled restoration of ion channel function in cultures of cells from cystic fibrosis (CF) patients and in a CF mouse model.

In cystic fibrosis, mutations of the CFTR (cystic fibrosis transmembrane conductance regulator) gene affecting chloride ion channel function lead to dysregulation of epithelial fluid transport in the lung, pancreas, and other organs. Complications include thickened mucus in the lungs with frequent respiratory infections, and pancreatic insufficiency giving rise to malnutrition and diabetes. These conditions lead to chronic disability and reduced life expectancy.


Gene therapy holds promise for a curative treatment applicable to all CF patients. The various viral vector-based clinical trials conducted in the past have demonstrated safety and tolerance of different vectors, but none have led to a clear and persistent clinical benefit. In the current study, investigators at KU Leuven (Belgium) described how recent clinical breakthroughs in adeno-associated virus-(rAAV) based gene therapy encouraged them to re-explore a rAAV approach for CF.

Adeno-associated virus (AAV) is a small, benign virus found in humans and some other primate species. The virus causes a very mild immune response, lending further support to its apparent lack of pathogenicity. Gene therapy vectors using modified AAV can infect both dividing and quiescent cells and persist in an extrachromosomal state without integrating into the genome of the host cell. These features make AAV a very attractive candidate for creating viral vectors for gene therapy.

The investigators evaluated the preclinical potential of rAAV gene therapy for CF to restore chloride and fluid secretion in two complementary models: intestinal organoids derived from CF subjects and a CF mouse model, an important milestone towards the development of a clinical rAAV candidate for CF gene therapy. Towards this end, they engineered a rAAV vector containing the gene for a truncated form of CFTR combined with a short promoter (CMV173) to ensure optimal gene expression.

Results of treatment of mice and cell cultures with the CFTR-rAAV vector were published in the October 28, 2015, online edition of the American Journal of Respiratory and Critical Care Medicine. They provided evidence that rAAV-mediated gene transfer of a truncated CFTR functionally rescued the CF phenotype across the nasal mucosa of CF mice and in patient-derived organoids.

"We administered the rAAV to the mice via their airways. Most of the CF mice recovered. In the patient-derived cell cultures, chloride and fluid transport were restored," said senior author Dr. Zeger Debyser, professor of molecular medicine at KU Leuven. "We must not give CF 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. Furthermore, we still have to examine how long the therapy works. Repeated doses might be necessary. But gene therapy clearly is a promising candidate for further research towards a cure for cystic fibrosis."

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