No effective therapies exist for Angelman's syndrome, a neurodevelopmental disorder that can cause seizures, sleep disorders, speech problems and motor control issues. Patients do not express a functional copy of the enzyme ubiquitin-ligase E3A (UBE3A), which marks old proteins in the brain for breakdown. As a result, proteins accumulate in the brain, interfering with neuronal function.

In rodents and humans, neurons express UBE3A only from the maternal copy because translation of the father's copy of the gene is repressed. The disorder is therefore the result of mutations or deletions in the maternal copy of the gene. People with Angelman's syndrome have a normal copy of the gene from their fathers, suggesting that 'un-silencing' the dormant paternal copy in neurons might prevent the disorder.

A group of researchers led by Benjamin D. Philpot at the University of North Carolina (Chapel Hill, NC) tested this idea. Using cortical neurons from mutant mice that were genetically engineered to fluoresce when UBE3A was turned on, they screened for molecules that could turn on the functional paternal copy of the gene. The screen identified several molecules that were able to 'un-silence' the father's copy of the gene in these cells (Nature doi:10.1038/nature10726; published online 21 December 2011).

The most promising of these drugs was topotecan, which is approved for the treatment of cancer in humans. In living transgenic mice that modeled the disease, the drug caused the father's copy of the gene to be expressed in neurons in several areas of the brain as well as in the spinal cord. The degree to which the gene was 'un-silenced' was correlated with the concentration of the drug in the brain. They also confirmed that the protein encoded by the 'un-silenced' gene functioned normally in the neurons. Further, a single course of treatment with topotecan could permanently modify expression of UBE3A. The scientists suggest that other diseases in which a functional copy of a gene is silenced could be targeted using a similar approach.

Topotecan is a promising treatment for Angelman's syndrome in humans because it is currently approved for use in adult and pediatric cancer patients, and it has a demonstrated ability to penetrate into the central nervous system. The researchers next need to test for off-target effects and to determine an optimum dosage of the drug.