• Dragana Vidović, Marianne S Carlon, da Cunha Mélanie F MF 2 INSERM U1151, University Paris Descartes, Faculté de Médecine Necker Enfants-Malades, Paris, France., 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, and Zeger Debyser.
• 1 Molecular Virology and Gene Therapy.
• Am. J. Respir. Crit. Care Med. 2016 Feb 1; 193 (3): 288-98.

RationaleGene therapy holds promise for a curative mutation-independent treatment applicable to all patients with cystic fibrosis (CF). 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. Recent clinical breakthroughs in recombinant adeno-associated viral vector (rAAV)-based gene therapy encouraged us to reexplore an rAAV approach for CF.ObjectivesWe evaluated the preclinical potential of rAAV gene therapy for CF to restore chloride and fluid secretion in two complementary models: intestinal organoids derived from subjects with CF and a CF mouse model, an important milestone toward the development of a clinical rAAV candidate for CF gene therapy.MethodsWe engineered an rAAV vector containing a truncated CF transmembrane conductance regulator (CFTRΔR) combined with a short promoter (CMV173) to ensure optimal gene expression. A rescue in chloride and fluid secretion after rAAV-CFTRΔR treatment was assessed by forskolin-induced swelling in CF transmembrane conductance regulator (CFTR)-deficient organoids and by nasal potential differences in ΔF508 mice.Measurements And Main ResultsrAAV-CFTRΔR transduction of human CFTR-deficient organoids resulted in forskolin-induced swelling, indicating a restoration of CFTR function. Nasal potential differences demonstrated a clear response to low chloride and forskolin perfusion in most rAAV-CFTRΔR-treated CF mice.ConclusionsOur study provides robust evidence that rAAV-mediated gene transfer of a truncated CFTR functionally rescues the CF phenotype across the nasal mucosa of CF mice and in patient-derived organoids. These results underscore the clinical potential of rAAV-CFTRΔR in offering a cure for all patients with CF in the future.

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