Scientists have known for a while that Angelman syndrome is caused by the loss of a specific gene, but they didn't understand how this gene loss leads to the failure of brain development in infants with the disease.
That's starting to change, thanks to work by researchers at Washington University School of Medicine in St. Louis. In a study published Oct. 21 in Nature, the researchers explained how they had identified the biological source that is tricking neurons into entering a stress response, leading to the symptoms of Angelman syndrome.
Angelman syndrome is a rare and severe neurodevelopmental disorder caused by loss-of-function of the maternal copy of the ubiquitin protein ligase E3A (UBE3A) gene. The paternal copy of the gene is normally silenced in Angelman syndrome by a phenomenon called genomic imprinting, a biological process where one copy of the gene is turned off.
Although this disorder is present since birth, children do not display typical symptoms—such as intellectual disability, facial dysmorphia, motor deficits and epilepsy—until six to 12 months of age. Angelman syndrome is not fatal, but individuals living with this disease typically require lifetime care.
The most unique aspect of the condition is the acquired microcephaly, or failure of the infant’s brain to develop and grow, resulting in a smaller head size and malfunctioning neurons.
The researchers at Washington University School of Medicine in St. Louis wanted to understand why losing the UBE3A gene leads to altered brain growth. In a mouse model that has UBE3A deleted, the researchers found that levels of asparagine synthetase were elevated and only present in neurons. The elevated levels of this enzyme triggered the integrated stress response (ISR) pathway, the cell’s emergency brake to pull if there is a threat present.
“Anytime the cell detects a threat, the first thing it does is conserve resources in case it has to fight that threat,” Jason Yi, Ph.D., assistant professor of neuroscience at Washington University School of Medicine in St. Louis and the study's lead study, told Fierce. “One of the first things that it does is halt protein synthesis.”
Halting synthesis stunts the growth of these neurons, leading to the behavioral phenotype seen in Angelman syndrome patients. The neurons are “tricked into thinking there is a threat or there is stress going on when there isn't,” Yi explained.
The identification of asparagine synthetase and the ISR pathway as crucial drivers of Angelman syndrome opens possible therapeutic avenues to explore, he suggested. “Right now, I think Angelman syndrome is a pretty active space for therapeutic development,” Yi noted.
Biotechs already operating in the space have tended to focus on antisense oligonucleotides (ASO) as therapies for Angelman syndrome. Rare disease biotech Ultragenyx recently reported a phase 3 fail for its ASO therapy aimed at preventing the silencing of the paternal copy of UBE3A. Oak Hill Bio and Ionis Pharmaceuticals are also attacking the same mechanism.