Researchers identify potential treatment for Angelman syndrome
A small molecule could lead to effective therapy for the rare genetic disorder, UNC School of Medicine scientists say.
Angelman syndrome is a rare genetic disorder caused by mutations in a maternally inherited gene that is characterized by poor muscle control, limited speech, epilepsy and intellectual disabilities. Though there isn’t a cure for the condition, new research at the UNC School of Medicine is setting the stage for one.
Unlike other single-gene disorders such as cystic fibrosis and sickle-cell anemia, Angelman syndrome has a unique genetic profile. Researchers have found that children with the conditions are missing the maternally inherited copy of the UBE3A gene, which regulates the levels of important proteins, while the paternally inherited copy of the UBE3A gene remains dormant. Missing a working copy of the gene leads to severe disruptions in brain development.
But what if the dormant copy of the gene could be activated?
Ben Philpot, the Kenan Distinguished Professor of Cell Biology and Physiology at the UNC School of Medicine and associate director of the UNC Neuroscience Center, and his lab have identified a small molecule that could be safe, noninvasively delivered and capable of “turning on” the dormant paternally inherited gene copy brain-wide. A kind of gene therapy, this potential treatment could lead to proper protein and cell function for individuals with Angelman syndrome.
“This compound we identified has shown to have excellent uptake in the developing brains of animal models,” said Philpot, a leading expert on Angelman syndrome and a member of UNC Lineberger Comprehensive Cancer 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.”
These results, published in Nature Communications, mark a major milestone in the field, according to Mark Zylka, the W.R. Kenan Jr. Distinguished Professor of Cell Biology and Physiology at the UNC School of Medicine and director of the UNC Neuroscience Center. No other small molecule compound has yet to show such promise for Angelman, he added.
Hanna Vihma, a postdoctoral research fellow in the Philpot lab and first author on the study, and colleagues screened more than 2,800 small molecules from a Pfizer chemogenetic library to determine if one could potently turn on paternal UBE3A in mouse models with Angelman syndrome.
One compound, (S)-PHA533533, shows promise, but 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. Along with medicinal chemists in the lab of Jeff Aubé, the Philpot lab is working to identify similar molecules with improved drug properties and safety profiles. “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.”
