Scientists awarded $7.7 million grant to develop treatment for rare brain disorder

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 both on parents and children, said Gavin Rumbaugh, Ph.D., a neuroscientist at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology.

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 is that their work will improve the quality of life for both children and adults with the disorder, Rumbaugh said. Collaborators on the grant include Wertheim UF Scripps scientists Courtney Miller, Ph.D., and Ted Kamenecka, Ph.D..

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

Gavin Rumbaugh, Ph.D., neuroscientist at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology

When working properly, the SYNGAP1 gene helps the brain assemble the circuits needed to process the senses and learn, Rumbaugh discovered. Mutations can impair this process, with varying outcomes. People have two copies of each gene. Often, a mutation that knocks out one working copy isn't a problem. But with SYNGAP1, losing both gene copies is fatal, and partial or complete loss of one copy can be debilitating, Rumbaugh said.

"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 said. "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."

Advocacy groups connecting families include the Syngap1 Foundation, and the SynGAP Research Fund.

The condition is rare. One estimate suggests that about 200 babies a year are born with a SYNGAP1 mutation in the United States. 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 said.

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. The scientists hope that a drug able to boost SYNGAP1 might benefit others types of patients as well. It's possible that people recovering from strokes, or people with brain and nervous system degeneration might also benefit, Rumbaugh said.

"Our work has shown that SYNGAP1 is a potent activator of neuroplasticity, or the ability to make new connections based on experience," Rumbaugh said. "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, said Miller, the institute's director of academic affairs, and a co-investigator on the project.

"To create a safe and effective first-in-human drug for the clinic, a lot of work must be done on the original molecule," Miller said. "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 said.

"We're excited and hopeful about the potential to improve the lives of people with this mutation, and possibly, others grappling with neuroplasticity issues," Rumbaugh said.

The research is supported by NIMH grant number 1U01MH136567-01.