Topotecan is a cancer medicine that may also be beneficial in people with Angelman syndrome (AS), a rare neurogenetic disorder marked by developmental delays, lack of language, seizures, and difficulties with balance and walking.

The disease is caused by a loss of function in the UBE3A gene. One copy of the UBE3A gene is inherited from each parent. In most tissues of the body, both copies of the gene are active. However, in certain areas of the brain, the paternal copy is silenced and only the maternal copy is active. AS occurs when the maternal gene does not function normally, leading to a deficiency in the proteins produced by this gene in the brain.

Topotecan research

Researchers have found that topotecan may be able to “awaken” the paternal UBE3A gene in places where it is normally silenced, potentially leading to a treatment for AS.

While screening drugs that are already approved by the U.S. Food and Drug Administration (FDA) for the treatment of other conditions, the researchers found that topotecan upegulated (increased the cellular response of) the expression of the UBE3A gene in a dose- and time-dependent manner in mouse nerve cells grown in the laboratory.

Topotecan inhibits the activity of an enzyme called topoisomerase 1, which controls and alters the DNA during transcription. The researchers found that topotecan reduced the amount of free topoisomerase 1 in cultured neurons, unsilencing the paternal UBE3A gene and resulting in an active protein.

Further studies are still needed to determine whether topotecan has a similar effect in human tissues and whether it can relieve symptoms of AS in animal models, before being tested in human clinical trials.

Other details

Topoisomerase 1 inhibitors are already used as anticancer agents to interrupt DNA replication leading to cancer cell death. Oral topotecan is currently used to treat small cell lung cancer and ovarian and cervical cancer.

Common side effects include nausea, diarrhea and vomiting, tiredness, and temporary hair loss. It may also lower white blood cell and platelet counts, making it easier to get an infection or bleed.

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