CRISPR treats stem cells from cystic fibrosis patients

cystic fibrosis symptoms
Image by Bruce Blaus via WikiCommons.

Scientists use CRISPR to ‘cure’ cystic fibrosis in gut tissue grown from patients. 

Cystic fibrosis is the most common life threatening genetic disease affecting 70 000 people worldwide. It is much more common in white people than in other races.  Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR gene). This gene makes a protein that sits in the cell membranes of cells in sweat and mucus glands. It allows chloride ions to flow out of cells into sweat or mucus. Since chloride is a negative ion, it also brings positive sodium and water with it. When this channel is absent or doesn’t work in cystic fibrosis patients, the mucus in their lungs and pancreas becomes sticky and clogs airways and pancreatic ducts. This is why these patients suffer from lung disease and digestive problems.

There have been many advances in cystic fibrosis treatment over the past fifty years. Babies with cystic fibrosis in the 1950s only lived on average to be six months old. Now people with cystic fibrosis can live to be in their forties and fifties. Most treatments only treat symptoms, not the underlying genetic cause. Scientists have been investigating gene therapy to edit out the mutations that cause this disease. This would allow patients to express normal CFTR channels and should hopefully cure them. Just 5-10% of the normal levels of functioning CFTR channels is enough to stop most symptoms. There are a couple of drugs on the market, Ivacaftor and Lumacaftor, that each target one of the cystic fibrosis causing mutations and tell the cell to skip the mutated region and make a normal protein. However, cystic fibrosis is caused by over 1500 different genes.

So scientists have recently enlisted the much lauded CRISPR gene editing system in the fight against cystic fibrosis. The scientists first took stem cells from cystic fibrosis patients. These patients carried the most common cystic fibrosis causing mutation – a mutation carried by 90% of cystic fibrosis patients in the US. They then used the CRISPR system to edit out the mutation in the stem cells. Then they grew these stem cells into mini-guts in lab dishes using a 3D culture technique. The treated mini-guts responded normally to a swelling test which showed that the CFTR chloride channel worked in the treated guts. Untreated mini-guts grown from patients did not swell at all in the test.

In a previous study, a different group of scientists grew mini-guts from mouse intestinal stem cells. They made these stem cells express various fluorescent proteins and then transplanted them into different mice that had intestinal damage. The transplanted mini-guts grew into the recipient mouse intestines and helped to repair their injuries. Treated mice gained more weight than mice that were not given the transplanted mini guts. The transplanted cells were still there 25 weeks later (scientists could tell because the mini-guts would fluoresce) and the surrounding intestine looked normal. There were no signs of cancer formation or other problems in intestinal structure.

So it seems to be possible to grow stem cells into mini-guts in the lab and then transfer them back into mice safely. However we don’t yet know whether this can be done in humans. That must be tested before CRISPR treatment of stem cells can be used to treat the intestines of cystic fibrosis patients. Also this approach would not treat other affected organs and lung disease is the most common cause of death in cystic fibrosis patients. Therefore, it will also be important to research into whether CRISPR can be used to treat lung cells in the same way.

The Scientific Papers:

Schwank et al. Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell. 2013 (free and open access!)

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