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Cell & Gene Therapy Insights

Cell & Gene Therapy Insights

Genome editing corrects cystic fibrosis in vitro

A collaborative research conducted by scientists at the University of Trento and KU Leuven has provided proof-of-concept for the use of CRISPR gene editing strategy in correcting mutations in cystic fibrosis patients.

Cystic fibrosis (CF) is a monogenic autosomal recessive disease caused by mutations in the CFTR gene, encoding a chloride channel. Decreased or absent functional CFTR protein in airway epithelial cells results in abnormally viscous mucus and impaired mucociliary transport, leading to bacterial infections and inflammation causing progressive lung damage.

Two gene mutations, the 3272–26A>G and 3849+10kbC>T CFTR mutations alter the correct splicing of the CFTR gene.

Several gene correction strategies have been tested to treat CF, the most advanced being CFTR gene delivery to the lungs to compensate patients’ defective CFTR gene. However, gene delivery approaches using viral and non-viral vectors have been hampered by the low and unstable expression of the gene in the affected tissues. This prompted scientists to investigate alternate strategies that could fix gene mutation permanently; and CRISPR nucleases has emerged as a potential candidate for gene therapy.

In the present study conducted by researchers at the University of Trento (Italy) and KU Leuven (Belgium), the teams developed a genome editing strategy using the precise programmable nucleases, AsCas12a, that permanently corrects CFTR splicing defects of at least two relevant splicing mutations (3272-26A>G and 3849+10kbC>T) in combination with a single crRNA.

The study published in Nature Communications has demonstrated that the AsCas12a-based gene correction strategy efficiently corrected the splicing pattern in human primary airway epithelial cells, a physiologically relevant 2-D model for CF disease. Complete functional recovery of the CFTR channel was also observed in the airway cells. The efficacy of the strategy was also confirmed in intestinal organoids from CF patients which are considered as valuable tools to evaluate CFTR channel activity and functional recovery.

Findings from the study demonstrate the efficacy of gene editing using the AsCas12a-crRNA nuclease system as a valuable tool to correct cystic fibrosis and open the possibility of testing the strategy for other genetic diseases caused by deep intronic splicing mutations.

Source: Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing. Maule G et al, Nature Communications, August 2019. DOI

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