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News: Genes & Cells Drugs activate dormant gene Chemotherapy agent may offer hope for treating Angelman syndrome By Tina Hesman Saey 5:15pm, December 21, 2011 Magazine issue: Vol. 181 #2, January 28, 2012, p. 8 HEALTHY GLOW The gene UBE3A normally manufactures protein throughout a mouse’s brain (green, above). But in animals with a version of Angelman syndrome, the maternal copy of the gene is faulty and the paternal copy is shut off, preventing the protein from being made (bottom). Philpot Lab, UNC Neuroscience Center 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.

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Article Summary

In the article “Drugs activate dormant gene” authors Huang et al. (2011) argued that kick-starting the UBE3A inherited genes could reverse the Angelman syndromes. Angelman genetic disorders affect over 1 in 15,000 births. The genetic disorder is mainly caused by the UBE3A gene inherited from the mother goes missing or becomes mutated while those from the father are already turned off. Thus, the formation of the UBE3A genes becomes problematic resulting in behavioral and physical complications. The UBE3A genes are often considered the imprinted genes and over the past year, the ability to override the imprinted genes and restore genetic activities was problematic and scientists resorted to gene therapy. The article offers a startling but unproven solution to Angelman genetic disorders.

Huang et al. (2011) in “Drug activates dormant genes” explained that a drug topoisomerase inhibitor can reverse the imprinted genes.  In this context, using a sample of mice with Angelman syndrome, reported achievements related to the efficacy of the drug in correcting the gene defect in Angelman have been met with excitement. Recent studies at the University of North Carolina used brain cells from the mice genetically engineered to detect any activation of the UBE3A genes of the father copy (Huang et al., 2011). During the study, over 2,000 chemicals were tested to predict any potential to turn on the inactivated gene from the father. One revelation during the study was that drugs that affected the DNA chemical tags did not restore the gene activity. But, instead, the DNA inhibiting drugs such as topoisomerase activated the gene activity. Thus, the study finding creates new avenues for future research on the roles of proteins in resetting imprinted genes.

Reference

Huang, H.-S., Allen, J. A., Mabb, A. M., King, I. F., Miriyala, J., Taylor-Blake, B., Sciaky, N., Dutton, J. W., Lee, H.-M., Chen, X., Jin, J., Bridges, A. S., Zylka, M. J., Roth, B. L., & Philpot, B. D. (2011). Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature, 481(7380), 185–189. https://doi.org/10.1038/nature10726

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