Fragile X Syndrome Neurons’ Function Restored with CRISPR/Cas9 Genome Editing

The gene-editing technology CRISPR/Cas9 was able to restore the expression of the FMR1 gene in nerve cells, the underlying cause of fragile X syndrome.

The study “Rescue of Fragile X syndrome neurons by DNA methylation editing of the FMR1 gene” was published in the journal Cell. 

The FMR1 gene in healthy people is composed of three nucleotides’ (our genome building blocks) repeats — CGG repeats — that vary in number from five to 55. Extending the number of repeats, from 56 to 200, increases the risk for developing some fragile X symptoms, but having more than 200 repeats is certain to cause the disease.

Researchers at Whitehead Institute speculated that the number of CGG repeats could be linked to the deposition of marks — called methylation — that silence the FMR1 gene.  

The team developed a modified version of the CRISPR/Cas9 system, a genome editing tool, to edit parts of the genome by removing, adding or altering sections of the DNA sequence. That  allowed the team to modulate the levels of methylation by either adding new methyl groups or removing them from specific pieces of DNA.  

By removing the methylation in the FMR1 gene, researchers could completely restore the levels of FRM1 in fragile X syndrome nerve cells generated from stem cells.

”These results are quite surprising — this work produced almost a full restoration of wild type expression levels of the FMR1 gene,” Rudolf Jaenisch, MD, said in a press release. Jaenisch is the study’s lead author and professor of biology at Massachusetts Institute of Technology.

Importantly, when these neurons were transplanted into the brains of mice, they were able to sustain FRM1 gene expression for at least three months. 

“We showed that this disorder is reversible at the neuron level,” said study first author, Shawn Liu, PhD. “When we removed methylation of CGG repeats in the neurons derived from fragile X syndrome iPS cells, we achieved full activation of FMR1.”

“This work validates the approach of targeting the methylation on genes, and it will be a paradigm for scientists to follow this approach for other diseases,” Jaenisch added.