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Drug Treats Inherited Form of Intellectual Disability in Mice

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Drug Treats Inherited Form of Intellectual Disability in Mice

A recent study at the Johns Hopkins University School of medicine have shown evidence that inherited form of intellectual disability may not be always irreversible. The researchers studied mice that had a genetic change similar to what is found in Kabuki syndrome “ a form of intellectual disability in humans. Then then used an anticancer drug to “open up” DNA which resulted in the improvement of mental functions.


Not only the study suggest a potential treatment for reversing the symptoms seen in Kabuki syndrome, the study also suggest a new way of treating a category of genetically inherited disease known as the Mendelian disorder. This category of disorder is characterized by mutation which errors in the way proteins and chemicals bind to DNA. This in turn affects the rate at which proteins is made by DNA. In their experiment on the mice which had Kabuki syndrome-like condition, the researchers noticed that those errors lead to a decrease in new cell growth in one part of the brain.  The decrease the say is however treatable.


The report on this research appeared online on October 1st in the journal Science Translational Medicine. The study was led by Bjornsson along with Harry “Hal” Dietz, M.D., the Victor A. McKusick Professor of Medicine and Genetics and director of the William S. Smilow Center for Marfan Syndrome Research.


In the Mendelian disorders of the epigenetic machinery the cell's ability to ‘package’ and use DNA is affected. Hence they tend to have complicated and far-reaching effects remarked Hans Bjornsson, M.D., Ph.D., an assistant professor of pediatrics and genetics in the Johns Hopkins University School of Medicine’s and McKusick-Nathans Institute of Genetic Medicine.  He further said that this finding that a drug could ease some of the symptoms in this group of disorders suggest that other such could be treated in a similar manner.


Bjornsson research focuses on Kabuki syndrome. This disorder is caused when there are mutations in one of two genes that govern proteins that DNA wrap around. The DNA is wound around the packaging proteins called chromatin. The formation of chromatin is necessary to fit in several feet of DNA inside the tiny centers from where commands are send to each cell. For a cell to be able to read the DNA and use it for making new proteins of its own, the chromatin must temporarily open up. Special enzymes are responsible for the opening and closing of the chromatin.


Based on some other recent studies, Bjornsson and his collaborators speculated that conditions like Kabuki syndrome might be due to an imbalance between chromatin’s open and closed states. Bjornsson added that if that assumption is proved to be true, it would mean that the disorders of the histone machinery could be treated by regulating balance between open and closed states.


To test the assumption, Joel Benjamin, a graduate student in Bjornsson's lab, experimented on mice.


The model mice had a mutation in one of the Kabuki syndrome genes and exhibited symptoms that are similar to Kabuki syndrome.


In their young adult phase, the mice were treated with AR-42, a drug developed for cancers of the blood that is known to open up compacted chromatin. Two weeks after the treatment, the mice were put through a drill called the Morris water maze, which tests their ability to form memories in the hippocampus region of the brain. The results showed that the treated mice performed better than the untreated mice almost at par with healthy mice.


Upon studying the brains of the treated mice, the researchers found that compared to untreated peers, they showed some formed neurons in a part of the hippocampus called the dentate gyrus, which is important for memory formation. The researchers came to the conclusion that when DNA’s chromatin opens up, the cells are able to ‘turn up’ one or more genes needed for that new growth.


Bjornsson remarked that now we know that new brain cells continue to form throughout our lives. So, stimulating neuron growth may be an effective strategy for treating intellectual disability.