A CRISPR cure for cystic fibrosis?

CRISPR-Cas9
Base editing is a CRISPR variation that allows for gene mutations to be repaired on-site without the need to cut out pieces of DNA. (Ernesto del Aguila III, National Human Genome Research Institute, NIH)

The gene-editing system CRISPR has generated plenty of excitement for its potential to correct genetic diseases, but because the technology involves cutting DNA, there are concerns about adverse effects. Scientists led by the Hubrecht Institute in the Netherlands say they’re perfecting a safer approach to CRISPR that doesn’t involve cutting DNA—and they have early evidence that it could be used to correct a gene mutation that causes cystic fibrosis.

The technique, called base editing, allowed the researchers to correct a mutation in the gene CFTR that causes the buildup of mucus in the lungs and other organs in cystic fibrosis. But instead of employing the enzyme Cas9 to cut the mutation out of the gene and then replacing it with a corrected piece—as would be done with traditional CRISPR editing—the Hubrecht team used base editing to repair the mutation on-site in stem cells from cystic fibrosis patients. They described the technique in the journal Cell Stem Cell.

“With the new base-editing technique the mutation in the CFTR gene can be detected and repaired without creating further damage in the genome,” said co-author Maarten Geurts, a biologist at Hubrecht Institute, in a statement.

RELATED: CRISPR edits out a deadly lung disease in mice before birth

To perform the study, the researchers turned to a biobank of intestinal organoids, which are miniature models of the gut that Hubrecht and UMC Utrecht created from stem cells taken from cystic fibrosis patients. They used the mini-guts to demonstrate that base editing can be performed on CFTR mutations.

The prospect of applying CRISPR to lung diseases has been proposed by other research institutions, including the University of Pennsylvania School of Medicine. Scientists there led a study that used CRISPR in mouse models to inactivate the genetic mutation that causes the lung disease surfactant protein C (SFTPC) deficiency.

Base editing, meanwhile, has generated enthusiasm in the biopharma startup community. Beam Therapeutics is using the technique to target diseases caused by “point mutations,” which are mutations that involve a single nucleotide base. After raising $135 million in a series B funding round last year, Beam pulled off a $180 million initial public offering.

Hubrecht’s Geurts warned that using base editing in the treatment of cystic fibrosis could ultimately prove challenging, because the disease affects more than just the lungs. So far, CRISPR has shown the most promise in diseases that affect just one organ or tissue type, such as sickle cell. So his team is planning further studies to determine whether base editing will be feasible in treating people with cystic fibrosis.

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