An “Unsilencer” Drug May Treat Angelman Syndrome – Someday

Angelman and Prader-Willi syndromes are intriguing related conditions. Each arises from missing the same small section of chromosome 15, but one develops if the gap comes from the female parent, the other if it comes from the male.

A Peculiar Pair of Disorders

Prader-Willi syndrome is the more distinctive, and therefore more likely to make headlines.

A newborn with Prader-Willi is small and struggles to put on weight. A toddler becomes obsessed with eating as metabolism slows precipitously. Frantic parents lock kitchen cabinets, garbage cans, and refrigerators to keep their children from eating until their digestive organs burst.

The brain’s hypothalamus malfunctions and can’t regulate appetite, and so children can’t sense when they are full. Plus, their stomachs do not empty quickly enough. The unremitting hunger becomes life-threatening.

In contrast, a child with Angelman syndrome has autism spectrum disorder and intellectual disability, an extended tongue, large jaw, poor coordination, and convulsions that make the arms flap. The distinctive facial features led Harry Angelman, when he described the condition in 1962, to call affected individuals “puppet children.” In 1982 “Angelman syndrome” replaced the derogatory puppet comparison.

Parental Chromosomal Sex Matters

A gene called UBE3A lies at the crux of both conditions. It is highly expressed in the brain – that’s where it’s encoded protein is most abundant.

If the gene is deleted (absent) in the copy inherited from the father, Prader-Willi syndrome results. The maternal copy remains, but is silenced, as it typically is if the father’s gene is present and active.

In contrast, if the gene is deleted in the copy inherited from the mother, Angelman syndrome results. The paternal copy remains, but it is silenced.

In both conditions, neighboring genes may be missing too. This part of chromosome 15 is especially unstable because highly repetitive DNA sequences bracket the genes associated with the symptoms. Repeats can cause slippage as DNA replicates.

A gene whose expression is absent or altered depending upon the gender of the parent-of-origin is said to be imprinted. In Prader-Willi and Angelman syndromes, a tiny section of the same chromosome is absent. Imprinting disorders can also result from differences between parental genders in gene expression – that is, protein production from the encoded information.

Imprinting is a clear example in which chromosomal sex – being XX or XY – is relevant to health. A transgender female could have a child with Prader-Willi syndrome, but not Angleman, because all cells have an X and a Y. 

Having both copies of UBE3A is important because the protein that it encodes cleans up cellular debris.

No Treatments

The complex imprinting aspect of both conditions has made treatments elusive. But now Ben Philpot and his team at the University of North Carolina Neuroscience Center have identified a small molecule that might counter the absence of the maternally-inherited UBE3A and surrounding genes. The clever mechanism? Activating the genes from the father that are normally silenced. The work is published in Nature Communications.

The researchers scrutinized a “chemogenetic library,” which is a collection of chemical compounds that bind to specific DNA sequences. The compounds therefore serve as probes.

The team screened 2,800 small molecules from Pfizer’s library for activators of the paternal UBE3A gene in mouse models of Angelman syndrome and in mouse nerve cells genetically modified to glow when the paternal UBE3A gene turns on. The researchers compared the many treated cells to the same cell types treated with topotecan, a different small molecule that activates paternal UBE3A but does not alleviate Angelman’s symptoms in mouse models.

And the investigators found a compound, for now called (S)-PHA533533, originally developed as an anti-tumor agent. Treated mouse neurons fluoresce. Plus, repeating the experiment using induced pluripotent stem cells derived from children with Angelman syndrome showed the same effect, indicating that the compound has clinical potential.

What’s more, the compound moves around the brain and persists awhile, possibly long enough to exert an effect on a disorder that affects growth and development.

“We previously showed that topotecan, a topoisomerase inhibitor, had very poor bioavailability in mouse models. We were able to show that (S)-PHA533533 had better uptake and that the same small molecule could be translated in human-derived neural cells, which is a huge finding. It means it, or a similar compound, has true potential as a treatment for children,” said first author Hanna Vihma.

The researchers call the potential drug candidate a “Ube3a unsilencer.” It’s an exciting first step to fighting a long-time puzzling, untreatable condition. They’re working with medicinal chemists to identify molecules that are similar to the unsilencer but have properties that make them better suited as a drug, in terms of safety and efficacy.

The unsilencer offers hope. Summed up project leader Benjamin Philpot, “This compound has shown excellent uptake in the developing brains of animal models. We still have a lot of work to do before we could start a clinical trial, but this small molecule provides an excellent starting point for developing a safe and effective treatment for Angelman syndrome.”

And that’s good news indeed!