CRISPR gene editing has been used to repair a genetic form of intellectual disability in human brain cells in a dish. If the same technique can be done in the brain, it may help treat a range of genetic conditions.
Fragile X syndrome is the most common inherited form of intellectual impairment, affecting one in 4000 men, and one in 6000 women. It is caused by having a silenced version of a gene called FMR1, which typically causes someone to be a slow learner and have behavioural issues like hyperactivity and limited attention.
The disorder has no cure, but there are hints that gene-editing techniques could help. Researchers have already shown by slicing out mutations using CRISPR. Now,听听at the Massachusetts Institute of Technology and his colleagues have found a way to reactivate the听FMR1听gene without having to alter its DNA sequence 鈥� an approach which may be safer and more ethical.
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Editing the epigenome
The team used an emerging technique called 鈥渆pigene-editing鈥� to edit the small markers that sit on DNA and turn genes on and off.
In people with fragile X syndrome, these markers keep the听FMR1听gene shut off. 听When the researchers cut these tags off using molecular scissors 鈥� similar to those used in CRISPR 鈥� the gene switched back on in brain cells derived from stem cells from people with fragile X syndrome. When the gene was turned back on, the neurons no longer displayed the overexcitability that disrupts the brain circuits of people who have the condition.
When the team injected these repaired neurons into the brains of five mice, they found that FMR1 remained active in 57 per cent of the cells for three full months.
The major advantage of epigene-editing over gene-editing is that it is reversible, says Jaenisch. That means any off-target effects could be fixed and wouldn鈥檛 be passed to future generations, he says.
Silenced genes
The team is now planning to test the technique directly in the brains of mice with fragile X syndrome, rather than implanting neurons that have been modified in a dish.
at the University of California, Davis, recently showed this was possible for Angelman syndrome 鈥� another genetic form of intellectual disability. His team managed to that causes the condition by applying epigene-editing directly to the brains of mice.
However, there are still many questions to answer about such techniques. It is unclear whether it would be possible to reverse fragile X syndrome in adults, or if you would need to switch FMR1 on at the embryo stage, says Jaenisch.
But if epigene-editing turns out to be technically feasible, it might be useful for treating other conditions caused by silenced genes, like Prader鈥揥illi syndrome and Rett syndrome, says Segal. It may even be useful for treating Alzheimer鈥檚 disease and Parkinson鈥檚 disease, since there is some evidence that the wrong genes are turned on and off in these conditions.
Cell
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