DALLAS – May 23, 2024 – A new study focused on the gene tied to a rare form of autism spectrum disorder (ASD) called FOXP1 syndrome offers hope that gene therapy might be able to help patients with this condition.

In a study published in Science Advancesresearchers from UT Southwestern Medical Center found that using gene therapy to restore the Foxp1 gene to adult mice from which it had been deleted before birth restored the activity of other genes whose levels are controlled by Foxp1. This intervention also corrected some abnormal behaviors characteristic of mice that lack Foxp1. The findings could shed light on other forms of ASD as well.

“The ability to partially remedy brain pathway changes at later developmental stages suggests that gene therapy may be effectively applied in FOXP1 syndrome and actually normalize symptoms,” said Genevieve Konopka, Ph.D., who co-led the study with Jay Gibson, Ph.D. Both are Professors of Neuroscience and Investigators in the Peter O’Donnell Jr. Brain Institute at UT Southwestern.

About 200 individuals worldwide have FOXP1 syndrome, a genetic condition caused by mutations in the FOXP1 gene that render it nonfunctional. Along with intellectual deficits, developmental delays, and other symptoms, people with this disease also tend to have ASD or exhibit autistic behaviors. But how the loss of FOXP1 contributes to these symptoms has been unclear, Dr. Gibson explained.

A key circuit that’s disrupted in FOXP1 syndrome connects regions of the brain called the cortex, thalamus, and striatum. To better understand FOXP1’s involvement in this circuit, Drs. Konopka and Gibson and their colleagues used a technique to delete this gene in mice in two populations of neurons in the striatum, which receives inputs from both the cortex and thalamus through a chemical called glutamate. Glutamate causes these neurons to fire when it’s taken up at structures called synapses that connect neurons.

In one population of neurons, the deletion altered the functions of thousands of other genes and caused changes in neuronal responses as well as significant differences in behavior; the animals had problems building nests and spent more time on the edges of their enclosures. When the researchers used a genetic technique to reinstate Foxp1, this intervention normalized how neurons responded to glutamate and restored activity in 78 genes, most known to function in neural synapses. It also normalized some behaviors, such as nesting and time spent in enclosures.  

Further study of this gene and the thousands of other genes it regulates could identify new targets for pharmaceuticals to treat this condition. Because some of these genes have also been implicated in other forms of ASD, continuing to study FOXP1 could lead to a better understanding and potential treatments for ASD in general, Dr. Konopka noted.

Other UTSW researchers who contributed to this study are first author Nitin Khandelwal, Ph.D., Instructor of Neuroscience; Ashwinikumar Kulkarni, Ph.D., Assistant Professor of Neuroscience; and Matthew Harper, M.S., Research Associate.

Dr. Konopka is a Jon Heighten Scholar in Autism Research and holds the Townsend Distinguished Chair in Research on Autism Spectrum Disorders.

This study was funded by grants from the National Institute of Mental Health (MH126481 and MH102603), the National Institute of Neurological Disorders and Stroke (NS126143 and NS115821), the James S. McDonnell Foundation 21st Century Science Initiative in Understanding Human Cognition — Scholar Award (220020467), and the Simons Foundation (573689).

About UT Southwestern Medical Center 

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

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