UNC STUDY COULD LEAD TO TREATMENT FOR ANGELMAN SYNDROME
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University of North Carolina at Chapel Hill researchers used a type of drug to awaken a dormant gene in mouse neurons and in living mice, thereby identifying a potential treatment strategy for doing the same in people with Angelman’s syndrome (AS), a developmental disorder related to autism.
The most characteristic feature of AS is the absence or near absence of speech throughout the person’s life. Occurring in one in 15,000 live births, other AS characteristics include intellectual and developmental delay, severe intellectual disability, seizures, sleep disturbance, motor and balance disorders. Individuals with the syndrome typically have a happy, excitable demeanor with frequent smiling, laughter, and hand flapping. No effective therapies exist for AS.
Angelman syndrome is linked to mutations or deletions in the Ube3a gene inherited from the mother, or the maternal allele. In most tissues of the body, both the maternal and paternal alleles are expressed. But in rodents and humans, the paternal Ube3a allele is intact but silent, or dormant.
After screening thousand of compounds in a library of FDA-approved drugs obtained from the National Institute of Health (the NIH Clinical Collection) the UNC team discovered that irinotecan, a topoisomerase (TOPO-EYE-SOM-ERASE) inhibitor known to be active in the central nervous system -- robustly ‘awakened’ the dormant paternal allele of Ube3a.
The team identified the cancer medications ironotecan and topotecan and several other topoisomerase inhibitors as drugs which can ‘awaken’ Ube3a. When neurons taken from mice genetically engineered to express a fluorescent version of the gene and were bathed in these drugs, the neurons would now glow, indicating that the dormant paternal allele was on.
And when topotecan was given to mice it unsilenced the paternal Ube3a allele in several regions of the nervous system, including neurons in several areas of the brain and in the spinal cord,” the authors state. These findings also held true for irinotecan. Importantly, the protein from the unsilenced paternal Ube3a was functional and was expressed by the gene in amounts comparable to that of normal maternal Ube3a in ‘control’ animals.
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