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Utrecht groups repair cystic fibrosis

A unique result: Utrecht researchers have genetically repaired cultured 'miniature intestines' or organoids of two cystic fibrosis (CF) patients in the laboratory. "It represents a key step towards stem cell therapy using genetically repaired cells for diseases caused by a single defective gene."

Researchers at the Hubrecht Institute and University Medical Center (UMC) Utrecht took a few intestinal stem cells from two children with cystic fibrosis. They then cultured these into 'miniature intestines' or organoids. These tiny cultured organs also carry the defective CF gene.

In a next step, the researchers repaired the defective gene in the cultured miniature intestines. As a result of this repair, the organoids act the same as the cultured organoids of healthy people. In other words, the tissue growing in the laboratory is the two CF patients' own intestinal tissue, but without the gene that causes the disease.

"Our study shows how powerful the combination of stem cell technology and genetic repair is," says lead researcher Prof. Dr Hans Clevers of the Hubrecht Institute. "In the future, this can be used for many diseases caused by a single defective gene, because we recently discovered how we can multiply the stem cells of most internal organs in the laboratory on a large scale. This technology appears particularly suitable for congenital metabolic disorders affecting the liver."

The cystic fibrosis gene was repaired by injecting a healthy specimen of the gene into the organoids. This smart genetic trick triggers the cells to replace the defective gene with the healthy one. It's like replacing an old file on your computer with a new file carrying the same name.

Multiple organs
Paediatric lung specialist Prof. Dr. Kors van der Ent of the Wilhelmina Children's Hospital/UMC Utrecht also collaborated in the study. "While the genetic repair of intestinal cells of CF patients is an extraordinary achievement, we are, unfortunately, still unable to cure cystic fibrosis, as this disease affects multiple organs. However, this new technology is a giant step forward compared to the other forms of gene therapy used for cystic fibrosis to date."

The researchers have previously demonstrated that the cultured organoids of CF patients can be used to test new medicines. Van der Ent: "We are now treating some of our patients with substances that we would otherwise never have considered."

In mice, it is now possible to repair damaged organs using cultured tissue. Clevers and his colleagues have already treated mice with cultured tissue from stem cells. They put back cultured intestinal and liver tissue in mice with intestinal or liver damage. The cultured tissue functioned normally.

1,200 CF patients in the Netherlands
Symptoms of cystic fibrosis include the accumulation of thick, sticky mucous, which causes problems in the lungs and intestines. There is no cure for the disease and CF patients have a limited life expectancy. There are an estimated 1,350 people in the Netherlands suffering from cystic fibrosis. Every year, some 40 infants are born with the disease. UMC Utrecht's Cystic Fibrosis Center treats about of these 450 patients.

Cystic fibrosis is caused by a genetic defect as a result of which a gate on the outside of cells does not function properly. This gate normally allows salt ions to pass through. In CF patients, this process does not work properly, which also has a negatively effect on fluid transport, causing thick and sticky mucous to build up.

The results of the study will be published in the journal Cell Stem Cell on December 5. The study is a collaboration between the Hubrecht Institute, the Royal Netherlands Academy of Arts and Sciences and the Wilhelmina Children's Hospital/UMC Utrecht.

Schwank G, et al. Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell 2013;13:653-658
06 December 2013