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Bench to bedside, Carolina leads study of Angelman syndrome

Research on the one defective gene that causes the rare autism-related disorder could lead to broader breakthroughs.


Jalazo family sitting on steps
Dr. Liz Jalazo, seen here in a family photo, is at the heart of Carolina’s concentrated research on Angelman syndrome. Her daughter Evelyn, now 8, (center of front row) was diagnosed with the rare disorder just before her first birthday. (Photo courtesy Liz Jalazo)

The frequent smiles and ready laughter of patients with Angelman syndrome mask the rare neurological disorder’s more serious symptoms. Severely developmentally disabled, most can’t talk and begin to walk at a later age with an awkward, jerky gait and often flap their hands. These are the traits that led English physician Dr. Harry Angelman to refer to them as “puppet children” in a 1965 paper. When two University of Florida researchers followed up on his work in the 1980s, they proposed that the disorder be named for Dr. Angelman.

The Angelman Syndrome Foundation embraced the serendipitous name, incorporating angel wings into its logo, and its website is filled with photos of smiling children. Irish actor Colin Farrell, whose son James has the disorder, has said that James’ constant “grinning from ear to ear” was what first tipped off a doctor to the problem.

Dr. Liz Jalazo

Dr. Liz Jalazo

Ironically, these frequent smiles and laughter often trigger worry in new parents, especially when their babies aren’t hitting developmental milestones on time, said pediatrician Dr. Liz Jalazo, chief medical officer at the foundation and assistant professor of pediatric genetics and metabolism in the School of Medicine.

As the father of child with Angelman syndrome recently told Jalazo, “I googled, ‘Why is my child always happy?’ And that’s what came up.”

Jalazo knew exactly what he meant because her work is at the heart of Carolina’s concentrated work with the rare disorder. A physician-researcher, she interacts regularly with three of the nation’s top Angelman researchers at the UNC Autism Research Center and at the UNC Comprehensive Angelman Syndrome Clinic, one of the first Angelman clinics in the country, established here in 2011.

Researchers concentrate on the rare disorder not only because they want to help the 500,000 people who have Angelman but also because they think the one defective gene that causes its symptoms could hold the key to other genetic mutations. If they can figure out how to solve the Angelman mutation, they can apply similar solutions to autism and other conditions with strong genetic underpinnings.

Research with impact

Here’s a roundup of some of Carolina’s Angelman syndrome studies:

“There’s a lot of attention on Angelman syndrome right now. It’s poised to be one of the first neurodevelopmental disorders where we have a potentially transformative treatment,” Jalazo said.

That’s especially important to Jalazo because she is also the mother of 8-year-old Evelyn, diagnosed with Angelman syndrome just before her first birthday. One of the first calls Jalazo made after the diagnosis was to Carolina, her alma mater. Specifically, she wanted to speak to leading Angelman researcher Ben Philpot, Kenan Distinguished Professor of cell biology and physiology in the School of Medicine and associate director of the UNC Neuroscience Center.

“He was incredible. And I’ve seen him do it 100 times over for any new family that I’ve sent his way. He was really a beacon of hope in such a challenging time,” Jalazo said.

Ben Philpot and Mark Zylka

Ben Philpot and Mark Zylka are among the top Angelman syndrome researchers in the country.

Building an A-team

Philpot, like most of Carolina’s Angelman researchers, started out studying something completely different. He was interested in the plasticity of the brain but learned about Angelman through a collaboration at Duke University.

His interest was purely academic until he attended his first Angelman conference. “You meet the families and the individuals with Angelman syndrome, and you just immediately fall in love with them,” he said. “They have infectious personalities, but they also face real challenges in their life. You just want to help them.”

Philpot redirected his research to focus on Angelman syndrome and began to assemble a team of experts in other fields to help. “There are a lot of advantages because we can all share our knowledge and our different approaches,” he said.

Dr. Bryan Roth

Dr. Bryan Roth

Mark Zylka, William R. Kenan Jr. Distinguished Professor of cell biology and physiology in the School of Medicine and director of the UNC NeuroscienceCenter, brought molecular and genetic expertise.  Dr. Bryan Roth, Michael Hooker Distinguished Professor of Protein Therapeutics and Translational Proteomics in School of Medicine’s pharmacology department, had drug discovery experience. Hiroyuki Kato, assistant professor of psychiatry in the School of Medicine, studies auditory processing. Adam Hantman, associate professor at the UNC Neuroscience Center, focuses on complex motor movements. Heather Hazlett and Mark Shen, both assistant professors of psychiatry in the School of Medicine, look at similarities and differences across several neurodevelopmental disorders. And Jalazo works primarily in clinical trials and sees patients with rare genetic disorders, including Angelman.

“UNC is just a place where people are willing to work together and try things. There aren’t big egos where people are trying to hoard all the glory,” Zylka said. “Academia is an incredibly competitive place. But that’s definitely not the situation here at UNC. People are actively working to promote one another’s careers and promote research in this area so that we can really make headway on this disorder.”

On the cusp of a treatment

Philpot’s lab is looking at two approaches, one using traditional gene therapy and the other using techniques to reactivate a dormant gene. The gene therapy approach uses a virus to replace the defective gene with a healthy one.

The reactivation approach is more particular to Angelman syndrome. A baby is born carrying two copies of the UBE3A gene (also associated with autism), one from each parent. In Angelman, the active copy from the mother mutates spontaneously. (No cause has been identified and it’s not considered an inherited syndrome for most.)

The copy from the father is dormant, so researchers are experimenting with ways to activate it to replace the defective maternal gene. Using a virus, DNA fragments, or a drug has already been shown to work in mice, suggesting that reactivation of paternal UBE3A can be done. Inspired by the research done at Carolina, three drug companies are currently running clinical trials on reactivating the dormant paternal copy of the gene, Philpot said.

Zylka’s lab has been working with CRISPR-Cas9 genome editing technology to reactivate the paternal gene, which worked in a mouse model. “The advantage of a genome editor approach is that it has the potential to be a one-time treatment,” Zylka said. Other therapies would require spinal injections every one to four months.

Evelyn Jalazo

Evelyn Jalazo (Photo courtesy Liz Jalazo)

Because Angelman syndrome is so tied to brain development, early treatment would be critical. Ideally, and with prenatal or newborn testing, treatment could begin at birth or soon after. For older children, treatment could still have dramatic results. “Recovery wouldn’t be instantaneous because you would have to provide training and let the synapses in the brain form properly. All kinds of therapy would be involved. But if you do this early enough in life, you should be able to provide a huge benefit,” Philpot said.

Carolina is currently enrolling two of the three gene reactivation trials. Each month when Angelman syndrome patients come to the clinic here to meet with specialists, they sign up to participate in available studies  and in the natural history study that gathers information about the disorder.

“It’s an incredibly educated, motivated community that wants to participate in clinical research,” Jalazo said. “There’s never been a more hopeful time to have a child diagnosed with Angelman syndrome.”

That cutting-edge research and access to clinical trials was a prime reason Jalazo and her family relocated to Chapel Hill — for Evelyn. Evelyn, who likes to ride her adaptive bike with the big training wheels, who can color with crayons for hours, who loves to give hugs.

“Really, she just wants to be one of the other kids. She wants to do what everybody else is doing,” Jalazo said.



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