Two UC Davis researchers have received grants totaling $1.6 million to advance their work to find an effective treatment for Angelman syndrome, a rare genetic disorder that causes seizures and sleep disturbances and inhibits language development.
David Segal, professor in the Department of Biochemistry and Molecular Medicine, received $1.1 million, and Joe Anderson, assistant adjunct professor in the Department of Internal Medicine, received $500,000 from the Foundation for Angelman Syndrome Therapeutics (FAST) to pursue two different approaches to developing treatments for the neurologic disease.
The grants, which are in addition to an earlier $140,000 FAST grant awarded to Segal and a $1.1 million California Institute for Regenerative Medicine (CIRM) grant awarded to a team of UC Davis researchers in July, bring the total funding to nearly $3 million and put UC Davis at the forefront of research into the disorder, which occurs in one in 15,000 births.
“The generous support from FAST and CIRM is recognition of the innovative molecular therapies being developed at UC Davis for Angelman syndrome,” Segal said. “The collaborative teams to do this work are here, the knowledge experts are here, and now these sponsors have given us the chance to really try and help kids with this disease."
Segal, a faculty member at the MIND Institute, is using his grant funding to further develop gene editing technology to reactivate a gene in the brain, known as Ube3a, which is silenced in Angelman syndrome.
Segal explained that Angelman syndrome is caused by the loss of expression of a protein normally made by the Ube3a gene that plays a critical role in the function of the nervous system. Segal’s lab has created a programmable transcription factor, a protein that can control gene function and manipulate gene expression, which in earlier research funded by FAST was shown to turn on the affected gene in mouse models of Angelman syndrome, he said.
Anderson, for his part, is working to restore the gene’s expression in the brain using gene-delivery technology. Specifically, he and his colleagues are working to genetically modify blood-forming stem cells to express the wild type form of Ube3a, and then engraft the modified cells to produce new cells that can deliver the protein to affected neurons. The research also aims to evaluate the safety and effectiveness of the delivery vehicles in both cell culture and animal models of the disease.
“If normal levels of expression of the Ube3a protein could be delivered to affected cells for the life of the patient, regression of the disease may be achievable,” Anderson said.
Paula Evans, chair and founder of FAST, said the UC Davis researchers are playing a vital role in developing cutting-edge therapeutics for the disorder.
“The commitment that Dr. Segal, Dr. Anderson and UC Davis have made to finding potential treatments and eventually a cure for Angelman syndrome has given many families hope,” she said. “A cure is no longer a matter of if, but when.”
The CIRM-funded research under way involves use of mesenchymal stem cells as a delivery vehicle for a gene-modifying protein that recognizes and binds to the specific gene sequence that causes Angelman and turns the gene “on” using artificial transcription factors.
Other members of the interactive and collaborative research teams include: Katherine Ferrara of the Department of Biomedical Engineering; Alice Tarantal of the Departments of Pediatrics and Cell Biology and Human Anatomy; Jill Silverman of the Department of Psychiatry and Behavioral Sciences and MIND Institute; Jan Nolta, director of the stem cell program and Institute for Regenerative Cures; and Kyle Fink, a post-doctoral student in the Nolta lab. Gregory Davis, research and development manager for genome engineering at the biotechnology company MilliporeSigma, also is working on Segal’s FAST grant research team.