VTC Professor Receives NIH Grant to Investigate Potential Therapy for DiGeorge Syndrome

The human brain begins to assemble soon after conception as increasing numbers of brain cells connect to create circuits throughout the brain.

Genes provide the blueprint, but sometimes the blueprint is incomplete, connections are not made and circuits fail -; sometimes long before the problem can be recognized, let alone solved.

This is the case with DiGeorge syndrome, also known as 22q11.2 deletion syndrome, a genetic condition affecting approximately one in 3,000 babies. It begins with the deletion of one of two copies of a small number of genes on human chromosome 22, the cascading effects of which include cardiovascular problems, problems with craniofacial development and, as children grow, autism spectrum disorders and schizophrenia. By the time these symptoms are recognized, the opportunity for medical intervention is long past.

But now Anthony-Samuel LaMantia, a professor at VTC’s Fralin Biomedical Research Institute, has identified a key factor in this chain of events that reflects a fundamental aspect of the initial error in the genetic blueprint in people with the disease. DiGeorge syndrome -; and a short period in this timeline where help might be possible.

LaMantia, director of the institute’s Center for Neurobiology Research and a faculty member of the College of Science, will explore tapping into this window of opportunity with a five-year, $3.4 million grant from the ‘Eunice Kennedy Shriver National Institute of Child Health and Human Development, part of the National Institutes of Health.

LaMantia’s research has the potential to inform new treatment strategies where none currently exist for autism and schizophrenia associated with DiGeorge syndrome. DiGeorge syndrome remains one of the few common genetic syndromes associated with a high risk of developing autism and schizophrenia later in life. Additionally, understanding the underlying disruption of brain development due to DiGeorge syndrome offers the opportunity to identify how these disorders might arise due to incomplete genetic instructions for building a brain.

LaMantia’s lab, one of the few in the world working on this problem, has studied DiGeorge syndrome for more than two decades. The lab dives deep into how the circuits of the brain are built to develop a precise understanding of the causes of the syndrome.

I think 20 years of research has provided a basis for thinking differently about this disease clinically. It is a neurodevelopmental disorder that disrupts very specific and identifiable stages of brain development. And we’re really trying now to look at one of the last stages of brain development that we think is most likely to be accessible to make adjustments without damaging other things.”

Anthony-Samuel LaMantia, Professor at the Fralin Biomedical Research Institute at the VTC

LaMantia believes that mitochondria -; cell power plants -; are essential for disrupting brain development in DiGeorge syndrome.

In a typical developing brain, the mitochondria of neurons in the cerebral cortex have enough energy to make long-distance connections to other parts of the brain and switch circuits on and off to make sure everything is working properly.

In DiGeorge syndrome, the mitochondria lack oxygen and lack the energy to make the necessary connections. The reason for this disruption can be attributed to several genes in the region of chromosome 22, which is deleted in DiGeorge syndrome. The imbalance of having only half the required amount of these genes, the proteins they encode, and the mitochondrial support they provide, underlies a failure to make enough connections during human development. brain and dysfunctional system.

Although many impacts of the syndrome occur before birth or before the disease can be diagnosed, the mitochondrial deficit that disrupts the establishment of these final connections occurs late enough in brain development to allow intervention.

“If you’re going to fix it, that’s probably the only viable place to fix it, and without causing other problems in the process,” LaMantia said. “It’s fortunate that these are mitochondrial changes, because you can support mitochondria through relatively simple and very safe means, including dietary supplements or more precisely targeted medications.”

LaMantia is also a professor in the Department of Biological Sciences at Virginia Tech in the College of Science. Co-investigators include Michael Fox of the Fralin Biomedical Research Institute and professor and director of Virginia Tech’s School of Neuroscience; Assistant Professor Shannon Farris, Assistant Research Professor Daniel Meechan, Associate Research Professor Gregg Crabtree and Associate Research Professor Thomas Maynard, all of the Fralin Institute for Biomedical Research. Allison Tegge, assistant research professor in the Department of Statistics at the College of Science, and Andrew Ottens, associate professor of anatomy and neurobiology at Virginia Commonwealth University.