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Developmental Biology - Cystic Fibrosis

Cibio Knocks Out Cystic Fibrosis

Gene editing permanently corrects two mutations that cause cystic fibrosis...

The approach adopted by the team of the University of Trento, led by Anna Cereseto, opens new perspectives in the treatment of cystic fibrosis, a genetic disease for which no cure is currently available. Research was carried out in collaboration with KU Leuven (University), in Belgium. The project benefited from two years funding amounting to 90,000 euro from the Italian foundation for research on cystic fibrosis Fondazione ricerca fibrosi cistica with the participation of the Cystic fibrosis association of Trentino.

Results of their study were published in Nature Communications.
Cystic fibrosis is caused by a mutation of the gene producing Cftr (the cystic fibrosis transmembrane conductance regulator), whose malfunctioning affects multiple organs, especially in the lungs.

The UniTrento/KU Leuven research team adapted the Crispr-Cas system, molecular scissors that are revolutionising biomedicine, to permanently edit at least two types of the mutation that cause cystic fibrosis. In particular, the technique is called "SpliceFix" as it fixes the gene while restoring the protein production mechanism at the same time.

Giulia Maule, doctoral student in Biomolecular sciences at the University of Trento and first author of the article, explains: "We devised a genome editing strategy based on Crispr-Cas to permanently remove two different mutations that cause the disease. Crispr-Cas works like a genomic scalpel to cut out mutated elements with extreme accuracy. We demonstrated that our repair strategy works on patient-derived organoids and with a high level of precision: it targets only mutated sequences, leaving non-mutated DNA untouched."

The young researcher underlines a novel aspect of the study: "Instead of animal models, we have used organoids that we developed from the patients' cells, a choice that allowed us to verify the efficacy of the molecular strategy in a context that is very similar to that of the patients with cystic fibrosis."

Cystic fibrosis is also called the invisible disease because it doesn't show on the outside, and yet it takes a huge toll on the lives of the people it affects. Most of all, the affected have lung and digestive problems.
The disease is inherited from parents. In Italy, about one in 25 people is a carrier. This means that a couple of carriers has one chance in four to have a child with the disease. There are about 6,000 people with cystic fibrosis in Italy, and 200 new cases every year.

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. The 327226A>G and 3849+10kbC>T CFTR mutations alter the correct splicing of the CFTR gene, generating new acceptor and donor splice sites respectively. Here we develop a genome editing approach to permanently correct these genetic defects, using a single crRNA and the Acidaminococcus sp. BV3L6, AsCas12a. This genetic repair strategy is highly precise, showing very strong discrimination between the wild-type and mutant sequence and a complete absence of detectable off-targets. The efficacy of this gene correction strategy is verified in intestinal organoids and airway epithelial cells derived from CF patients carrying the 327226A>G or 3849+10kbC>T mutations, showing efficient repair and complete functional recovery of the CFTR channel. These results demonstrate that allele-specific genome editing with AsCas12a can correct aberrant CFTR splicing mutations, paving the way for a permanent splicing correction in genetic diseases.

Giulia Maule, Antonio Casini, Claudia Montagna, Anabela S. Ramalho, Kris De Boeck, Zeger Debyser, Marianne S. Carlon, Gianluca Petris and Anna Cereseto.

The authors are grateful to Daniele Arosio for helpful discussion throughout the development of this study and to Liesbeth De Keersmaecker for her excellent technical assistance. We thank Francesca Demichelis and Davide Prandi for continuing support in GUIDE-seq analyses. This work was supported by the Italian Cystic Fibrosis Foundation grant FFC#1/2017 adopted by Associazione Trentina Fibrosi Cistica in ricordo di Maria Cainelli e Romana Petrolli, delegazioni FCC di Imola e Romagna, di Alborello, Lucca, and by intramural funding from the University of Trento. We are grateful to Primary Cell Culture Serviceof the Italian Cystic Fibrosis Research Foundation at the Laboratory of Medical Genetics, G. Gaslini Institute, Genova, Italy, for CF primary cells. Work at the KU Leuven was supported by grants from the King Baudouin Foundation, Belgium [Fund Alphonse and Jean Forton, 3M140231] and a KU Leuven C3 grant OPIT-CF.

Competing Interests
G.M., A.Ca., M.S.C., G.P. and A.C. are listed as inventors on a patent application related to this work. A.C. and G.P. are scientific advisor to Alia Therapeutics. A.Ca. and G.P. are cofounder af Alia Therapeutics. A.Ca. is a current employee of Alia Therapeutics. The remaining authors declare no competing interests.

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Aug 8 2019   Fetal Timeline   Maternal Timeline   News  

TOP LINE 12-year-old girl with advanced Cystic fibrosis disease.
BOTTOM LINE 9-year-old boy with healthy lungs.
CREDIT European Respiratory Journal

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