Drugs ID’d in Mice to Possibly Treat Angelman SyndromeLast Updated: December 28, 2011. Reactivating the functional but silenced paternal allele of the ubiquitin protein ligase E3A may offer a possible treatment strategy for the severe neurodevelopmental disorder known as Angelman syndrome, according to an experimental study published online Dec. 21 in Nature.
WEDNESDAY, Dec. 28 (HealthDay News) -- Reactivating the functional but silenced paternal allele of the ubiquitin protein ligase E3A (Ube3a) may offer a possible treatment strategy for the severe neurodevelopmental disorder known as Angelman syndrome, according to an experimental study published online Dec. 21 in Nature.
Hsien-Sung Huang, Ph.D., from the University of North Carolina School of Medicine in Chapel Hill, and colleagues investigated whether Angelman syndrome could be treated by activating the epigenetically silenced paternal Ube3a allele to reestablish functional Ube3a protein. A library of drugs approved by the U.S. Food and Drug Administration were used to perform unbiased, high-content screening of primary cortical neurons obtained from mice.
The investigators found that the paternal Ube3a allele could be unsilenced by 12 topoisomerase I and four topoisomerase II inhibitors, which included topotecan, irinotecan, etoposide, and dexrazoxane. In neurons from maternal Ube3a-null mice, topotecan (at nanomolar concentrations) upregulated catalytically active Ube3a and downregulated Ube3a antisense transcript expression that overlaps the paternal Ube3a copy. In vivo topotecan administration unsilenced the paternal Ube3a allele in neurons from several regions of the nervous system, including the hippocampus, neocortex, striatum, cerebellum, and spinal cord. In a subset of spinal cord neurons, paternal Ube3a expression elevation persisted for at least 12 weeks after stopping topotecan treatment.
"Although potential off-target effects remain to be investigated, our findings suggest a therapeutic strategy for reactivating the functional but dormant allele of Ube3a in patients with Angelman syndrome," the authors write.