Experts will search for molecular therapies for SYNGAP1 syndrome, which impacts brain development
The RDM Positive Impact Foundation is funding an ambitious $1.25 million research project at the UC Davis MIND Institute to study SYNGAP1. The rare genetic condition causes seizures (epilepsy), intellectual disability and developmental delays. It is also highly associated with autism; about half of all SYNGAP1 patients have an autism diagnosis.
Ron Mittelstaedt and his wife, Darin run the foundation. He's the executive chairman of Waste Connections, a solid waste and recycling company with 20,000 employees in North America, and his family operates Toogood Estate Winery in Somerset. The Mittelstaedts have donated millions of dollars to organizations that help children over the past 15 years.
This time, it's personal.
About three and-a-half years ago, Ron Mittelstaedt's best friend died, leaving behind three sons and their families. "I've become sort of a surrogate dad, and now a surrogate grandfather," explained Mittelstaedt. One of those "grandsons" was diagnosed with a SYNGAP1 mutation a year and-a-half ago. With the family's support, Mittelstaedt is providing meaningful funding to the MIND Institute to advance research about the syndrome.
"The reality is, like many rare conditions, there aren't a lot of great options. So, we're trying to find potentially life-changing treatment that hopefully may impact the lives of people with SYNGAP1," he said.
Mittelstaedt was previously on the MIND Institute's inaugural National Council of Visitors (then called the MIND Institute Advisory Council), and funded a successful research project that developed a blood test for Tourette syndrome.
"We are grateful to the Mittelstaedts for their generosity," said MIND Institute Director Leonard Abbeduto. "As a collaborative hub for preclinical and clinical research on neurodevelopmental disability, the MIND Institute is uniquely suited to build on past successes and tackle the complexities of SYNGAP1 to provide help for families."
The funding also supports UC Davis' $2 billion fundraising campaign, Expect Greater: From UC Davis, For the World, the largest philanthropic endeavor in university history. Together, donors and UC Davis are advancing work to prepare future leaders, sustain healthier communities, and bring innovative solutions to today's most urgent challenges.
What is SYNGAP1?
SYNGAP1-related non-syndromic intellectual disability is a rare neurodevelopmental condition caused by a variation in one gene. The gene, SYNGAP1, contains instructions for making a protein (SynGAP). This protein is located at the junctions between nerve cells, called synapses, and helps regulate changes important for memory and learning. The protein also helps regulate communication between neurons.
When the variation is present, the SYNGAP1 protein in cells is reduced which causes an increase in the excitability in the synapses. This makes it difficult for neurons to communicate and increases the likelihood of seizure events. This can lead to a variety of symptoms:
* Developmental delay * Intellectual disability * Poor muscle tone, including trouble with balance and walking * Epilepsy * Sensory processing challenges * Autism * Sleep and behavior challenges.
SYNGAP1 syndrome affects 1-4 out of 10,000 people. The first patient was identified in 2009.
Groundbreaking research
The MIND Institute's interventional genetics team includes faculty who specialize in multiple research areas. "Each of us is a world expert in our particular discipline, so bringing us all together means the chances of success are much more likely," said Jill Silverman, associate professor in the Department of Psychiatry and Behavioral Sciences and an internationally recognized expert in the use of rodent models for therapeutic development. Silverman's Lab is known for its expertise in behavioral neuroscience research.
In addition to Silverman, the SYNGAP1 team includes three other MIND Institute faculty members:
* Kyle Fink, assistant professor in the Department of Neurology, the UC Davis Stem Cell Program, and the Gene Therapy Center. * David Segal, member of the UC Davis Genome Center. Segal also holds joint appointments in the Departments of Biochemistry and Molecular Medicine and Pharmacology. * Alex Nord, associate professor in the Departments of Neurobiology, Physiology and Behavior and Psychiatry and Behavioral Sciences, as well as the Center for Neuroscience and the Genome Center.
"The sum of the group is going to be much greater than anything we could have done alone," said Fink, whose lab focuses on therapeutic development for neurodevelopmental conditions and neurodegenerative diseases. "The fact that the foundation has funded us as a team, across multiple centers and programs is really unique. This funding brings us all together for an important project."
The researchers will work on parallel tracks, each contributing a piece of the puzzle.
Silverman will conduct specialized behavioral tests on mouse models of SYNGAP1, using tools with corresponding metrics in humans, such as EEGs (a type of brain scan) to determine clinically relevant outcomes. Nord and Fink will create a new mouse model that contains the mutated human SYNGAP1 gene, while Segal and Fink will create new molecular therapies to counter that mutated gene. They'll also figure out how to deliver those therapies to the brain.
"We're not just trying to treat the symptoms of the disease with a drug," explained Segal, whose lab specializes in molecular analysis. "We are trying to change the underlying genetic condition, and our particular approach is to do that in a way that does not change the DNA sequence. We use tools to change the gene expression instead, which we think will make safer therapies. It's really a state-of-the-art approach. It's molecular therapy."
The collaborative approach, often called "team science," coupled with the RDM Positive Impact Foundation's support, allows for an ambitious, fast-tracked research program. The $1.25 million frees the researchers from the need to apply for multiple federal grants and enables them to focus immediately on SYNGAP1.
The team excels in what's often called "bench to bedside" research, translating results from the lab directly into therapies for patients.
"We see these patients, we meet with them, we're on Zoom calls with them and I want to find something that works for them. I want to change their lives. That's what I'm driven by," Silverman said.
Building on previous success
Silverman, Fink and Segal have had previous success with their work on another rare genetic condition, Angelman syndrome, which causes developmental delay, speech and balance challenges and intellectual disability.
Their labs helped to create and characterize the first rat model of Angelman syndrome last year. The Segal lab also created a protein therapeutic that could increase the level of the affected gene in mouse models of Angelman syndrome, a major discovery. All three labs are still working on a wide range of therapeutics for Angelman, including molecular therapies delivered with viruses or stem cells and novel small molecule compounds.
Ron Mittelstaedt is hoping for another success story, this time with SYNGAP1, but he's also realistic about the research process.
"We are all very aware that going down this path doesn't guarantee anything except the ability to get up to bat, and we could get a hit or strike out. But doing nothing guarantees you don't get a hit, so it's important for us to take action, and we're hopeful we'll hit a home run."
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Original public release: https://www.eurekalert.org/news-releases/778331
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