UC Davis scientists pioneer stem cell gene therapy for Angelman syndrome
By Marianne Russ Sharp
Groundbreaking research on the rare neurodevelopmental condition is funded by California’s stem cell agency
(SACRAMENTO)
UC Davis Health researchers are testing a new gene therapy that could be transformational for patients with Angelman syndrome, a rare neurodevelopmental condition. The promising treatment could reduce or even eliminate symptoms by replacing a missing protein with a functional one.
From left, Professor of Psychiatry and Behavioral Sciences Jill Silverman and Associate Professor of Internal Medicine Joseph Anderson are collaborating on the project.
Angelman syndrome appears in early childhood. Common features include developmental delays, intellectual disability, seizures, speech challenges and problems with movement and balance. Angelman occurs in about 1 in 15,000 live births. There is no effective treatment or cure.
Angelman syndrome is caused by the loss of functional UBE3A gene in the brain. The gene provides instructions to make a protein called ubiquitin protein ligase E3A. When this protein is missing, nervous system function is impaired.
A groundbreaking new approach for neurodevelopmental conditions
The new gene therapy involves modifying a patient’s bone marrow blood stem cells — called hematopoietic stem cells — to deliver a functional version of the gene to the brain.
These cells could potentially reverse, stop or even prevent the symptoms of Angelman syndrome.
“We use the immune system as a delivery vehicle to express and then deliver the functional form of the protein,” Anderson explained.
The therapy may require only one treatment to work.
Leveraging the patient’s own biology to deliver therapeutics is a powerful technique that can eliminate unwanted or problematic effects.
In their initial study, published in 2021, Silverman and Anderson showed that the therapy reversed the Angelman phenotype in adult mouse models and prevented it in very young mouse models. The fact that it worked in both age groups was a major breakthrough.
“Previous studies have emphasized that beyond very early in life, Angelman syndrome symptoms cannot be reversed, and our study contradicted that evidence and prior ‘dogma’ of the field,” Silverman said.
The new study is focused on the safety of the therapy, in the hopes of moving it to human clinical trials next.
“This is the first time someone has attempted to use this strategy for a neurodevelopmental condition,” Silverman explained. “Hematopoietic stem cell therapy is common for genetic lysosomal storage disorders, blood, immune and other diseases, but no one has ever done it in this area.”
From left, Silverman and Anderson in front of Aggie Square, UC Davis' Innovation District, where Silverman has a lab.
Striking the right protein balance
The therapy is designed to be precise. Too little UBE3A can cause Angelman syndrome. But too much can lead to another neurodevelopmental condition called Dup15q syndrome. The team has worked carefully to find the right balance.
“This is a Goldilocks situation,” Silverman said. “We need just the right amount of the protein — not too little, not too much.”
That is why a key part of the new research involves studying the expression of UBE3A in the treated mice.
“The FDA wants us to look at the expression of UBE3A in our treated animals to ensure we have the right balance,” Anderson explained.
Silverman added: “We are measuring behaviors and impacts that have a direct patient benefit, an under-studied area that our labs have focused on for a long time.”
A perfect pairing
Silverman has a long history of research on Angelman and Dup15q syndromes and other genetic neurodevelopmental conditions. She is part of a team at the UC Davis MIND Institute that is focused on bringing innovative treatments from the research lab to the patient’s bedside as quickly as possible.
Anderson’s expertise is in stem cell gene therapy development for diseases like HIV and Tay-Sachs disease, a genetic disorder that affects the central nervous system.
“Joe is an immunologist and virologist, while I’m a neuroscientist, but we both are translational scientists, at heart,” Silverman said. “We just want our labs’ work to help affected children.”
“If this works, it opens up a whole new world of possibilities and hope for patients and families,” Silverman said.
The UC Davis MIND Institute in Sacramento, Calif. is a unique, interdisciplinary research, clinical, and education center committed to deepening scientific understanding of autism and other neurodevelopmental conditions. It is a highly collaborative center, bringing together families, researchers, clinicians, community leaders and volunteers with the common goal of developing more personalized, equitable, and scientifically proven systems of support and intervention. The institute has major research efforts in autism, fragile X syndrome, chromosome 22q11.2 deletion syndrome, attention-deficit/hyperactivity disorder (ADHD) and Down syndrome. More information about the institute and its Distinguished Lecturer Series, including previous presentations in this series, is available on the Web at https://health.ucdavis.edu/mind-institute/.
