NIH Grants $6.1M to Genetic Research in Angelman Syndrome at University of North Carolina

The National Institutes of Health (NIH) has awarded two grants totalling $6.1 million to support two research projects: one focused on the development of a new gene therapy for Angelman syndrome, and the other on understanding how genetic defects in UBE3A (the gene that causes Angelman) may be linked to autism.

Both projects are led by Mark Zylka, PhD, director of the University of North Carolina (UNC) Neuroscience Center, whose research has focused on understanding the mechanisms behind neurodevelopmental disorders and developing new therapies to treat patients with chronic pain and autism.

The first project, which will focus on the development of a new gene therapy based on the gene-editing tool CRISPR/Cas9, has received a $2.8-million grant from the National Institute of Neurological Disorders and Stroke.

The main goal of the project is to use CRISPR/Cas9 to turn on the normally inactive paternal copy of the UBE3A gene to replace the abnormal maternal copy that is responsible for Angelman syndrome. Researchers will test the feasibility of the new gene therapy in mice and human neurons cultured in a lab dish.

“There is currently no effective treatment or cure for Angelman syndrome,” Zylka, the W.R. Kenan Distinguished Professor of Cell Biology and Physiology, said in a news release.

“Our research will provide the first preclinical evidence that CRISPR/Cas9 can be used to enduringly ‘unsilence’ the paternal UBE3A gene in mice and ‘unsilence’ paternal UBE3A in cultured human neurons,” he said. “This new knowledge has the potential to advance a first-of-its kind treatment for a pediatric-onset autism spectrum disorder.”

This is the second time that Zylka has received financial support for this project. Last year, the Angelman Syndrome Foundation donated $200,000 to support the development of the new CRISPR/Cas9-based gene therapy for Angelman syndrome.

The second project, which will focus on understanding how genetic mutations in UBE3A may contribute to certain characteristics of autism, has received a $3.3-million grant from the National Institute of Mental Health.

This project will be carried out by Zylka in collaboration with Ben Philpot, PhD, associate director of the Neuroscience Center at the UNC School of Medicine, whose research has focused on investigating the mechanisms behind neurodevelopmental disorders, such as Rett and Angelman syndromes, and developing new treatments for them.

The second project will build on data from a previous study published by Zylka and his team in the journal Cell, which showed that certain genetic mutations in UBE3A may lead to the overactivation of ubiquitin protein ligase E3A, the enzyme that is encoded by the UBE3A gene, thereby causing autism.

“Our research will evaluate the extent to which UBE3A gain-of-function contributes to progenitor cell proliferation, proteasome dysfunction, and other autism-related phenotypes [characteristics],” Zylka said. “This new knowledge could point towards a new therapeutic strategy for autism — one based on rebalancing UBE3A and proteasome function in the developing brain,”

Of note, the proteasome is a complex of enzymes, including ubiquitin protein ligase E3A, that is responsible for the destruction of unnecessary or damaged proteins in cells.

The $6.1-million grant supporting both projects follows the announcement earlier this year of $6.8 million in funding from the National Institute of Environmental Health Sciences for another eight-year research project, also led by Zylka.

This eight-year project will focus on investigating how the interactions between genetic and environmental factors may contribute to the development of certain neurodevelopmental disorders, including autism and attention deficit disorder.