Small molecule could help treat Angelman syndrome

Researchers at the University of North Carolina at Chapel Hill, led by Professor Ben Philpot, have identified a small molecule that could lead to a safe and effective treatment for the neurodevelopmental condition known as Angelman syndrome — a rare genetic disorder characterised by poor muscle control, limited speech, epilepsy and intellectual disabilities. Their work has been published in the journal Nature Communications.

Unlike other single-gene disorders such as cystic fibrosis and sickle-cell anaemia, Angelman syndrome has a unique genetic profile. Researchers have found that children with the condition are missing the maternally inherited copy of the UBE3A gene, while the paternally inherited copy of the gene remains dormant in neurons, as it does in neurotypical individuals. Typically, UBE3A helps regulate the levels of important proteins; missing a working copy leads to severe disruptions in brain development.

For reasons that aren’t fully clear, the paternal copy of UBE3A is normally ‘turned off’ in neurons throughout the entire brain — which means that when the maternal copy of the UBE3A gene is mutated, this leads to a loss of UBE3A protein in the brain. Theorising that turning on this paternal copy would lead to proper protein and cell function, researchers in Philpot’s lab screened more than 2800 small molecules from a Pfizer chemogenetic library for one that could be applied to paternal UBE3A in mouse models with Angelman syndrome.

The researchers genetically modified mouse neural cells with a fluorescent protein that glows when the paternal UBE3A gene is turned on. After treating the neurons with more than 2800 small molecules for 72 hours, they compared their thousands of treated cells against those treated with topotecan, a known small molecule that can turn on paternal UBE3A but lacked therapeutic value in animal models of the condition.

(S)-PHA533533, a compound that was previously developed as an anti-tumour agent, caused neurons to express a fluorescent glow that rivalled that induced by topotecan, meaning that its effect was potent enough to successfully turn on paternal UBE3A. The researchers were able to confirm the same results using induced pluripotent stem cells derived from humans with Angelman syndrome, indicating that this compound has clinical potential.

Additionally, the researchers observed that (S)-PHA533533 has excellent bioavailability in the developing brain, meaning it travels to its target with ease and sticks around. This is notable in that previous genetic therapies for Angelman syndrome have had more limited bioavailability.

“We previously showed that topotecan, a topoisomerase inhibitor, had very poor bioavailability in mouse models,” said Dr Hanna Vihma, the first author on the study. “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.”

Although (S)-PHA533533 shows promise, the researchers are still working to identify the precise target inside cells that causes the desired effects of the drug. Philpot and colleagues also need to 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,” said Philpot, who is a leading expert on Angelman syndrome. “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.

“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.”

Image shows a five-month-old baby girl diagnosed with Angelman syndrome. Image credit: Vanderbilt University.