Small molecule shows promise as Angelman syndrome treatment

(S)-PHA533533 was first developed as a possible cancer therapy

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A molecule dubbed (S)-PHA533533 is able to increase the expression of the UBE3A protein in mouse and human cell models of Angelman syndrome, a new study shows.

“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,” Ben Philpot, PhD, a professor at the University of North Carolina School of Medicine and study co-author, said in a press release. The study, “Ube3a unsilencer for the potential treatment of Angelman syndrome,” was published in Nature Communications. The work was sponsored in part by Pfizer and The Angelman Syndrome Foundation.

Angelman syndrome is caused by mutations in the UBE3A gene, which provides instructions to make UBE3A. Everyone inherits two copies of the gene, one from each parent, but only the copy inherited from the mother is active in the brain; the copy from the father is inactive.

Angelman develops if the maternal copy of the gene is mutated. Since the paternal copy is inactive, a defective version of the maternal gene means no UBE3A can be produced. But that paternal copy is still there, silent. Reactivating it to allow UBE3A production is seen as a promising potential strategy for Angelman syndrome.

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A ‘huge finding’ in treating Angelman syndrome

Scientists used a nerve cell model to run a screen of more than 2,800 chemicals owned by Pfizer to look for molecules that could increase production of UBE3A from the paternal gene copy. The screen identified (S)-PHA533533 and both the molecule itself and some of its analogues were able to promote production of UBE3A from the paternal gene in nerve cells where the maternal copy was mutated.

(S)-PHA533533 was originally created as a possible cancer therapy to inhibit two related proteins called CDK2 and CDK5, but the researchers showed its effects on UBE3A were independent of those targets.

After identifying (S)-PHA533533 as a possible therapy, the researchers tested it in an Angelman syndrome mouse model and found the compound was able to get into the brain of mice and turn on production of UBE3A from the inactive paternal gene.

“This compound we identified has shown to have excellent uptake in the developing brains of animal models,” Philpot said.

The ability to get into the brain well sets (S)-PHA533533 apart from topotecan, another molecule found to increase paternal UBE3A expression, but that has limited therapeutic use because it can’t be delivered into the brain where it’s needed.

“We previously showed that topotecan … had very poor bioavailability in mouse models. We were able to show that (S)-PHA533533 had better uptake,” said Hanna Vihma, PhD, a postdoctoral fellow in Philpot’s lab and the first author of the study.

Further tests using nerve cells from people with Angelman syndrome showed consistent results, indicating the molecule is effective in human cells, not just mice. This is “a huge finding,” that suggests (S)-PHA533533 “has true potential as a treatment for children,” Vihma said.

The findings suggest “(S)-PHA533533 provides us with a powerful tool to be leveraged toward developing a transformative, noninvasively delivered therapeutic for” Angelman syndrome, said the researchers, who acknowledged there’s still a long way to go before the therapy can be moved into clinical tests. The scientists are now studying how (S)-PHA533533 modulates paternal UBE3A expression and are looking for similar molecules with better safety and pharmacological profiles that could be used in people.

“This is unlikely to be the exact compound we would take forward to the clinic,” Philpot said. “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.”