By kick-starting a gene that is naturally inactivated, chemotherapy drugs could help reverse a genetic brain disorder that is sometimes mistaken for autism or cerebral palsy. The unexpected finding may also spark a new avenue of research on a type of gene regulation known as imprinting.
The genetic disorder, Angelman syndrome, occurs in about one in 15,000 live births. It is caused when the copy of a gene called UBE3A inherited from the mother goes missing or is damaged by a mutation. That’s a problem because the copy of the gene inherited from the father is already turned off in brain cells, leaving no way to make UBE3A protein.
Genes such as UBE3A that turn off one parent’s copy are called imprinted genes. Until now, researchers knew of no way short of gene therapy to override the imprinting and restore gene activity.
Now, researchers from the University of North Carolina at Chapel Hill have discovered that a type of chemotherapy drug called topoisomerase inhibitors can turn on the father’s inactive copy of the gene in brain cells of mice with a version of Angelman syndrome. The team reports the achievement online December 21 in Nature.
The prospect that a drug could correct the underlying defect responsible for Angelman syndrome is exciting, says Stormy Chamberlain, a geneticist at the University of Connecticut Health Center in Farmington. “There’s every reason to have hope that it will help our Angelman syndrome kids,” she says.
Angelman syndrome is linked to severe developmental delays that keep people from attaining vocabularies of more than a few words. People with the disorder are apparently always cheerful and may laugh and smile inappropriately and have uncoordinated movements, as well as other physical and behavioral characteristics.
Charles Williams, a University of Florida pediatrician and geneticist who chairs the Angelman Syndrome Foundation’s scientific advisory committee, is also enthusiastic about the finding. “It’s a seismic shift. It is a really important breakthrough,” he says. “Having said that, a lot of us in the Angelman syndrome community are really worried that our expectations will not be met.”
Researchers don’t yet know whether the drugs can restore UBE3A production in human brain cells, or if turning the gene back on will reverse abnormalities in Angelman syndrome mice. More work with mice will be needed to determine whether the gene must be activated at some particular time during development, or if restoring gene activity can reverse the disorder at any time. Also, the drugs might inactivate other genes that should remain on in order to maintain health, producing unwanted side effects.
Clinical trials should not be attempted in people with Angelman syndrome, Williams says. Speaking on behalf of the foundation, he says, “We are very keen at this point that clinical trials not be prematurely started.”
For the new study, University of North Carolina neuroscientist Benjamin Philpot and his colleagues used brain cells from mice genetically engineered so their cells make a fluorescent protein whenever the father’s copy of UBE3A is active. The researchers tested more than 2,000 chemicals to see whether any could turn on the dad’s copy of the gene.
Most imprinted genes are tagged with chemicals either on the DNA or on associated proteins, so the researchers were surprised to find that drugs that affect those chemical tags didn’t restore the gene’s activity. Instead, drugs that inhibit the activity of DNA-unwinding proteins called topoisomerases did the trick.
DNA-unwinding proteins have never been implicated in imprinting before, so the discovery is likely to generate lots of new research on how the proteins are involved in the process, says Yong-hui Jiang, a clinical geneticist and neurobiologist at the Duke University School of Medicine. “Whether it’s working on resetting imprinting is an open question,” he says.