Angelman syndrome is caused by mutations in the UBE3A gene inherited from the mother and is characterized by poor muscle control, limited speech, epilepsy and intellectual disability, the researchers explained in the study published in the journal Nature Communications.
Ben Philpot, PhD, Kenan Distinguished Professor at the UNC School of Medicine, and his laboratory have identified a small molecule that could be administered safely, noninvasively, and capable of "switching on" the brain's copy of the inherited UBE3A gene. latently. -wide, which would lead to proper protein and cell function, which would amount to a kind of gene therapy for people with Angelman syndrome.
"This compound that we identified has been shown to have excellent uptake in the developing brains of animal models," said Philpot, a leading expert on Angelman syndrome.
According to the researchers, UBE3A helps regulate the levels of important proteins; Losing a functional copy causes serious alterations in brain development.
The researchers screened more than 2,800 small molecules to determine whether paternal UBE3A could be potently activated in mouse models of Angelman syndrome.
They found that a compound - PHA533533, which was previously developed as an anti-tumor agent - caused neurons to express a fluorescent glow that rivaled that induced by topotecan, meaning that its effect was potent enough to successfully activate 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, the study mentions.
Additionally, they noted that -PHA533533 has excellent bioavailability in the developing brain, meaning it travels to its target easily and stays.
"We were able to show that -PHA533533 had better uptake and that the same small molecule could be translated into neuronal cells of human origin, which is a great finding," said Hanna Vihma, PhD, first author of the study.
Ben Philpot, PhD, Kenan Distinguished Professor at the UNC School of Medicine, and his laboratory have identified a small molecule that could be administered safely, noninvasively, and capable of "switching on" the brain's copy of the inherited UBE3A gene. latently. -wide, which would lead to proper protein and cell function, which would amount to a kind of gene therapy for people with Angelman syndrome.
"This compound that we identified has been shown to have excellent uptake in the developing brains of animal models," said Philpot, a leading expert on Angelman syndrome.
According to the researchers, UBE3A helps regulate the levels of important proteins; Losing a functional copy causes serious alterations in brain development.
The researchers screened more than 2,800 small molecules to determine whether paternal UBE3A could be potently activated in mouse models of Angelman syndrome.
They found that a compound - PHA533533, which was previously developed as an anti-tumor agent - caused neurons to express a fluorescent glow that rivaled that induced by topotecan, meaning that its effect was potent enough to successfully activate 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, the study mentions.
Additionally, they noted that -PHA533533 has excellent bioavailability in the developing brain, meaning it travels to its target easily and stays.
"We were able to show that -PHA533533 had better uptake and that the same small molecule could be translated into neuronal cells of human origin, which is a great finding," said Hanna Vihma, PhD, first author of the study.
