CRISPR breakthrough may enable treatment for genetic diseases

The breakthrough could pave the way for use of the technology to treat human diseases like diabetes, kidney disease and muscular dystrophy.

By Brooks Hays

Dec. 8 (UPI) -- Scientists have modified the CRISPR/Cas9 genome editing technology to edit genes without creating gaps in the genetic code. The breakthrough could pave the way for use of the technology to treat human diseases like diabetes, kidney disease and muscular dystrophy.

CRISPR/Cas9 technology relies on the creation of double-strand breaks, or DSBs, in the genomic regions targeted for manipulation. Scientists have used the technology to augment the genes of a variety of species, but most scientists have voiced opposition to creating such breaks in the human genome.


In a new proof-of-concept study, detailed this week in the journal Cell, researchers with the Salk Institute for Biological Studies showed they could use CRISPR technology to treat human diseases in mice without causing DSBs.

"Although many studies have demonstrated that CRISPR/Cas9 can be applied as a powerful tool for gene therapy, there are growing concerns regarding unwanted mutations generated by the double-strand breaks through this technology," lead study author Juan Carlos Izpisua Belmonte, a professor in Salk's Gene Expression Laboratory, said in a news release. "We were able to get around that concern."


As an alternative to the live version of the enzyme Cas9, which is used with guide RNAs to create breaks in the genome, scientists developed a "dead" form of Cas9, dubbed dCas9. The new enzyme allows scientists to target regions of the genome for editing, but without creating a gap in the code.

Instead of cutting and splicing DNA, dCas9 is coupled with the molecular switches, called transcriptional activation domains, that turn DNA on and off.

Adeno-associated viruses are typically used to carry Cas9 to the gene-editing target, but AAVs do a poor job of shepherding dCas9 because the enzyme is too big and bulky.

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To develop a new technique for clinical trials, scientists combined parts of the old and new CRISPR/Cas9 methods. Scientists combined Cas9 or dCas9 into one AAV, and packaged molecular switches and guide RNAs in the other.

"The components all work together in the organism to influence endogenous genes," said study co-author Hsin-Kai "Ken" Liao, a staff researcher in the Izpisua Belmonte lab.

Scientists demonstrated their new technology in mice. Researchers targeted genes controlling insulin-producing cells in mice with type 1 diabetes. They also targeted genes controlling kidney function and encouraged the expression of genes linked with the reversal of muscular dystrophy symptoms.


"We were very excited when we saw the results in mice," said co-author Fumiyuki Hatanaka, a research associate in the lab. "We can induce gene activation and at the same time see physiological changes."

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