Researchers have identified a class of compounds that, when administered to mouse models of Angelman syndrome, activate production of a brain protein whose absence causes this relatively rare condition. Often classified as an autism spectrum disorder (ASD), Angelman syndrome is marked by developmental delay, lack of speech, seizures and motor difficulties. The study, led by neuroscientist Ben Philpot, Ph.D., of the University of North Carolina, Chapel Hill, appears in the online edition of the journal Nature.
The compounds that the researchers identified belong to a class of chemicals known as topoisomerase inhibitors. The main focus of the paper is on topotecan (brand name Hycamtin), which is already on the market as an FDA-approved treatment for small cell lung cancer that fails to respond adequately to first-line chemotherapy medicines. Like most chemotherapy medicines, it can be toxic to healthy as well as cancerous cells and can produce dangerous side effects such as bone marrow suppression. In addition, topotecan can cause fetal harm when administered to pregnant women.
The researchers screened over 2,300 compounds to identify several that restored production of the ubiquitin protein ligase E3A (UBE3A) in mouse brain cells and spinal cord tissue. In essence, the compounds activated a normally silent gene that compensated for a mirror gene that is disabled in Angelman syndrome.
Further testing is needed to determine if the compounds have a similar effect in human tissues and whether they actually relieve symptoms in animal models of Angelman syndrome. If the results of such tests are positive, one of the next steps would be to determine the minimum dose to produce beneficial effects while also avoiding serious side effects. Given the potential toxic effects of this class of compounds, further safety testing will be of paramount importance before these experimental medicines move into clinical trials in individuals with Angelman syndrome.
“While we’re heartened by the progress these early findings represent, there can be no shortcuts when it comes to safety in drug development,” says Joseph Horrigan, M.D., Autism Speaks’ assistant vice president and head of medical research. For more perspective on today’s news, please see a special blog by Dr. Horrigan and Eileen Braun, executive director of the Angelman Syndrome Foundation.
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