Angelman syndrome (AS) is a rare genetic disorder characterized by poor muscle control, limited speech, epilepsy, and intellectual disabilities. There is no cure for the disorder, named after Harry Angelman, MD—who first reported the syndrome in 1965.

Angelman syndrome is caused by mutations in the maternally inherited copy of the UBE3A gene. Paternal UBE3A is epigenetically silenced by a long non-coding antisense (UBE3A-ATS) in neurons. Therefore, when the maternal copy is mutated, UBE3A protein in the brain is eliminated. However, the reactivation of paternal UBE3A is a possible approach for treating AS.

Now, researchers have identified a small molecule that could be safe, non-invasively delivered, and capable of turning on the dormant paternally-inherited UBE3A gene copy brain-wide, which would lead to proper protein and cell function.

Hanna Vihma
Hanna Vihma, PhD
[Philpot Lab]

This work is published in Nature Communications in the paper, “Ube3a unsilencer for the potential treatment of Angelman syndrome.

Together with colleagues, Hanna Vihma, PhD, a postdoctoral research fellow in the Philpot lab at UNC School of Medicine, screened more than 2,800 small molecules from a Pfizer chemogenetic library to identify one that could activate paternal UBE3A in mouse models with Angelman syndrome.

Researchers genetically modified mouse neural cells with a fluorescent protein to indicate activation of UBE3A. After treating the neurons with more than 2,800 small molecules for 72 hours, researchers compared their cells with those treated with topotecan, a small molecule known to turn on paternal UBE3A. (Topotecan lacks therapeutic value in animal models of the condition.)

(S)-PHA533533, a compound that was previously developed as an anti-tumor agent, was found to act “through a novel mechanism to significantly increase paternal Ube3a mRNA and UBE3A protein levels while downregulating Ube3a-ATS in primary neurons derived from AS model mice.”

Angelman syndrome
Neurons with a fluorescent reporter for paternal UBE3A gene activity show only a background low fluorescent glow when treated with a vehicle control, but show a bright fluorescent glow when treated with (S)-PHA533533, indicating that the small molecule potently activated the dormant paternal allele of UBE3A. [Vihma et. al 2024]

Researchers were able to confirm the results using induced pluripotent stem cells derived from humans with Angelman syndrome. Additionally, researchers observed that (S)-PHA533533 has excellent bioavailability in the developing brain. The authors add that, “peripheral delivery of (S)-PHA533533 in AS model mice induces widespread neuronal UBE3A expression.”

“We previously showed that topotecan, a topoisomerase inhibitor, had very poor bioavailability in mouse models,” said Vihma. “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.”

“This compound we identified has shown to have excellent uptake in the developing brains of animal models,” said Ben Philpot, PhD, professor of cell biology and physiology at the UNC School of Medicine and associate director of the UNC Neuroscience Center. “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.”

Although (S)-PHA533533 shows promise, researchers are still working to identify the precise target inside cells that causes the desired effects of the drug. Philpot and colleagues will also conduct further studies to refine the medicinal chemistry of the drug to ensure that the compound—or another version of it—is safe and effective for future use in the clinical setting. “This is unlikely to be the exact compound we would take forward to the clinic,” continued Philpot. “However, this gives us a compound that we can work with to create an even better compound that could be moved forward to the clinic.”

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