Working to reverse Rett Syndrome

With a $750,000 grant from Rett Syndrome Research Trust, Michael Green is working to reverse a debilitating neurological disease
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UMass Medical School scientist Michael R. Green, MD, PhD, globally known for his work in gene regulation, keeps the image of Chelsea and that of other girls who suffer from Rett in mind as he works toward finding a drug that would reverse the disease. Dr. Green, a Howard Hughes Medical Institute Investigator, the Lambi and Sarah Adams Chair in Genetic Research and professor of molecular medicine and biochemistry & molecular pharmacology, received a $750,000 grant from RSRT for research aimed at reversing the underlying cause of the disorder. He is one of several dozen researchers around the world, recruited by Coenraads, who have met children with Rett and their parents, and are working on therapies, a cure or a reversal of the disease.
Rett syndrome is caused by a mutation of the gene on the X chromosome called MECP2 that causes numerous devastating symptoms that worsen over time. The symptoms begin in early childhood and leave Rett sufferers completely dependent on 24-hour-a-day care for the rest of their lives. While the function of MECP2 remains elusive, scientists know that it acts globally and impacts numerous systems in the body.
Female cells have two X chromosomes and therefore two copies of the MECP2 gene, and mutations occur in only one of the two copies of the gene. In females, however, one of the two X chromosomes is randomly turned off (or silenced), a phenomenon called X chromosome inactivation (XCI). As a result, in patients with Rett syndrome, half of the cells express a normal copy of MECP2 and the other half express the mutant copy. Importantly, in those cells that express the mutant MECP2, the normal copy is still present-just silent. Green is testing drugs that modulate XCI to reactivate the silent normal MECP2 gene in these cells as a strategy to reverse the disease.
"He is taking a somewhat unconventional approach, as he is attempting to reactivate the entire X chromosome and not just MECP2," said Coenraads. "His work first came to RSRT's attention in 2009. We learned that he was conducting a screen to identify genes that control XCI. As his work matured over the next few years he did indeed identify factors that control XCI, some of which belong to molecular pathways for which there are drugs. These drugs can now be tested in culture and in vivo in Rett syndrome mouse models."
Green praised the support he has received from RSRT and said the work that Coenraads and her colleagues do is inspirational.