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A team of researchers from the University of North Carolina has identified a potential treatment for Angelman syndrome, a rare genetic disorder. The breakthrough, detailed in a study published on Monday in the journal Nature Communications, offers new hope for individuals affected by this debilitating condition.
Angelman syndrome, caused by mutations in the maternally inherited UBE3A gene, is characterized by poor muscle control, limited speech, epilepsy, and intellectual disabilities. Researchers at UNC have discovered a small molecule that may safely and non-invasively activate the dormant paternally-inherited UBE3A gene copy throughout the brain, potentially restoring proper protein and cell function. This could represent a significant advancement in gene therapy for Angelman syndrome.
Dr. Ben Philpot, the Kenan Distinguished Professor at the UNC School of Medicine and a leading expert on Angelman syndrome, led the research. “This compound we identified has shown to have excellent uptake in the developing brains of animal models,” said Philpot. “We are hopeful that this could lead to effective treatments for individuals with Angelman syndrome.”
The study involved screening over 2,800 small molecules to find one capable of activating the paternal UBE3A gene in mouse models. The researchers identified (S)-PHA533533, a compound originally developed as an anti-tumor agent, which demonstrated potent effects. Neurons treated with (S)-PHA533533 exhibited a fluorescent glow comparable to that induced by topotecan, indicating successful activation of the paternal UBE3A gene.
Further validation came from experiments using induced pluripotent stem cells derived from humans with Angelman syndrome. The same potent effect of (S)-PHA533533 was observed, underscoring its clinical potential. Additionally, the compound showed excellent bioavailability in the developing brain, meaning it effectively reaches its target and remains active.
“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,” said Dr. Hanna Vihma, the study’s first author.
The discovery of (S)-PHA533533 as a potential treatment for Angelman syndrome marks a significant step forward in the search for effective therapies. With further research and clinical trials, this compound could offer a new avenue of hope for those affected by this rare genetic disorder.
