Boosting the Brain

Gavin Rumbaugh, Ph. D., and colleagues have been awarded a five-year, $7.7 million grant to develop potential treatments for severe autism, seizures and intellectual disability. SCOTT WISEMAN / WERTHEIM UF SCRIPPS

Children born with a damaged gene needed for healthy brain development, SYNGAP1, experience seizures, sensory processing disorders, difficulty speaking, intellectual disability and autism-like behaviors.

It’s a condition without any treatments, one that’s hard on parents and children, explains Gavin Rumbaugh, Ph.D., a neuroscientist at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology in Jupiter.

Rumbaugh and a team of scientists from the institute have been awarded a five-year grant from the National Institute of Mental Health worth $7.7 million to work toward a treatment. Their goal is to create a pill that restores healthy SYNGAP1 gene production, thereby boosting neuroplasticity, or the ability of the brain to form circuits and connections.

The scientists hope their work will improve the quality of life for children and adults with the disorder.

“Seizures can be induced in these children by something as simple as eating the wrong texture of food,” Rumbaugh says. “The benefit of a medication you could take as a pill is that the dose could be adjusted as the children grow.”

Rumbaugh discovered when working properly, the SYNGAP1 gene helps the brain assemble the circuits needed to learn and process the senses. Mutations can impair this process.

“Children born with the most serious SYNGAP1 mutations may have many seizures a day, difficulty walking, difficulty communicating, and difficulty sensing pain. Some require caregivers for their entire lives,” he says. “It’s only in recent years, with more available genetic sequencing and social media, that families have begun to find each other, enabling studies that estimate the prevalence of the mutations.”

The condition is rare. One estimate suggests that in the United States, about 200 babies a year are born with a SYNGAP1 mutation. Since its discovery in 2009, more than 1,000 people have been diagnosed. Up to 2% of people with intellectual disability may have a SYNGAP1 mutation, Rumbaugh says.

The new grant from NIMH’s National Cooperative Drug Discovery/Development Groups for the Treatment of Mental Disorders division will enable the scientists to refine their work on oral medicines to restore SYNGAP1 levels. Rumbaugh says a drug that is able to boost SYNGAP1 might also benefit other types of patients. It’s possible that people recovering from strokes or people with brain and nervous system degeneration might also benefit.

“Our work has shown that SYNGAP1 is a potent activator of neuroplasticity, or the ability to make new connections based on experience,” Rumbaugh says. “Because our experimental therapeutics stimulate SYNGAP1 expression, we expect that if our development process creates drug candidates with the desired properties, they will be useful in the SYNGAP1 genetic disorder, but they may also assist with other disorders that affect intellectual functioning.”

The Wertheim UF Scripps Institute is unusual because on one campus, experts in neurobiology can collaborate with experts and tools required to design medicines, explains scientist Courtney Miller, the institute’s director of academic affairs and a co-investigator on the project.

“To create a safe and effective first-inhuman drug for the clinic, a lot of work must be done on the original molecule,” Miller says. “This is a well-defined, iterative process of modifying the starting molecule, measuring how that affects the drug’s properties, like the ability to get into the brain, followed by ensuring it will be well-tolerated in humans.”

Ultimately, the hope is their therapy will remove many of the challenges faced by families affected by SYNGAP1 and, potentially, other brain disorders, Rumbaugh says. “We’re excited and hopeful about the potential to improve the lives of people with this mutation, and possibly, others grappling with neuroplasticity issues.”

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