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Researchers Fine-tune Disrupted Brain Circuitry With Focal Gene Therapy

Published on October 29, 2020 in Cornerstone Blog · Last updated 3 months 3 weeks ago


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Fine-tuning disrupted brain circuitry.

Researchers are using chemogenetic therapy to fine-tune problematic brain circuitry.

By Barbara Drosey

A collaborative research team at Children’s Hospital of Philadelphia and the University of Pennsylvania suggests in a new paper that a focal, molecular approach that targets circuit excitability may prove to be an effective intervention for treatment-resistant symptoms of mental illness.

In the healthy brain, neurons are firing in a range of their activity spectrum to optimally perform their functions. The research team is interested in identifying circuits that normally underlie critical brain functions, and then comparing them to instances of abnormal brain function in neurologic and psychiatric disease models. They want to see if circuit disruptions could account for behavioral manifestations associated with the conditions. Once they identify what’s gone wrong with the circuit, they are studying the effectiveness of focally introducing “designer” receptors to correct the deficit.

The scientists used this approach to identify hyperactive brain circuitry that affects social and spatial memory functions in an animal model of the 22q11.2 deletion syndrome (22q11DS). They then corrected the circuit hyperactivity using focal gene therapy that also resolved the functional problem, thereby improving social and spatial memory.

Stewart Anderson, MD, associate chair of research, Department of Child and Adolescent Psychiatry and Behavioral Services, and associate director of the Lifespan Brain Institute at CHOP and the University of Pennsylvania, and Douglas Coulter, PhD, CHOP investigator and professor of Pediatrics at the Perelman School of Medicine at Penn, and colleagues published findings from their cross-disciplinary project in Biological Psychiatry.

22q and Mental Illness

Many patients with 22q11DS experience intellectual and psychiatric challenges, and 20 to 30 percent of children with 22q11DS will develop schizophrenia in their late teens or early adulthood.

“Their risk is more than 20 times higher than the general population,” Dr. Anderson said. “Individuals with the 22q deletion account for 1 to 2 percent of all people with schizophrenia.”

Finding non-pharmaceutical interventions for individuals with 22q deletion and psychiatric disorders is especially challenging, which is why this patient population is front-of-mind in their research.

“Patients with 22q have multiple medical conditions which makes balancing side effects when medicating them for psychiatric purposes more complicated, as their various medical conditions can challenge their treatment strategy,” Dr. Anderson said. “The challenges with any medication, and an important underlying premise for this paper, is the idea that a patient can take a pill, and it's only going to have effects on specific molecular switches that are related to the particular brain circuitry that's disrupted by mental illness.”

With billions of circuits operated by thousands of switches, it's nearly impossible for a medication to target a specific circuit without having side effects. This research and projects like it are attempting to explore a new way of thinking: If investigators can identify where a circuit is disrupted, they can rebalance that circuit in a focal way that avoids the negative effects of medication distributed through the body.

While Dr. Anderson’s research focuses on the molecular and cellular mechanisms that govern the development of the mammalian forebrain and understanding the neuropathology of schizophrenia, Dr. Coulter’s work focuses on physiological studies examining mechanisms of epilepsy to better understand the underlying determinants driving seizure disorders. Both have the goal of identifying more effective treatments for various devastating neurologic conditions.

“Our goal is to return disrupted or diseased brain circuitry to its optimal tuning range,” Dr. Coulter said. “My lab was exploring this hypothesis by pushing the boundaries of a circuit’s optimal range. Our hypothesis was that nudging the circuit too far in one direction or the other would disrupt its behavioral output. We had developed this concept of fine-tuning disrupted circuitry over various studies, and were beginning to understand the translational impact of these kinds of changes, when this collaborative opportunity presented itself.”

Dr. Anderson shared his interest in following up previous collaborative studies involving transplantations of inhibitory neurons with Dr. Coulter, whose investigation of the 22q animal model was uniquely relevant to the 22q and You Center at CHOP for children who have hyperexcitability of the same hippocampal circuit he’s investigating. While translating their research from the lab to clinic is in the future, there is the potential to modulate social and spatial memory in patients with 22q11DS.

“This work suggests that brain circuit activity normalization by focal gene therapy in adults may be a promising treatment of neuropsychiatric abnormalities when they respond poorly to medication or when medication side effects are problematic,” said Dr. Anderson, who is also co-leader of the Developmental Biology Research Affinity Group at CHOP and professor of Psychiatry at the Perelman School of Medicine.

In the Balance

Ventral hippocampal hyperactivity is associated with psychosis — the reduced capacity to distinguish between real and imagined external and internal stimuli. Chemogenetic technology — the use of novel medications that selectively target genetically modified receptors — is making it more possible to correct abnormal circuitry and to change the related behaviors, even in an adult animal model of the disease with a developmental origin to their brain dysfunction.

“My lab has been working with these concepts for several years in numerous neurologic and psychiatric models of these disorders,” Dr. Coulter said. “Given my interest in the neuronal circuits and understanding how their function fails in psychiatric and neurologic disease, this collaboration and partnership proved fascinating.”

The approach would certainly not serve as a complete cure for schizophrenia in human patients, but it has potential to alleviate some of the more devastating aspects by rebalancing circuits related to some major symptoms.

An important component of this approach for treatment purposes is its modifiability. Following an acute initial therapy during which a genetically modified receptor, developed using an adeno-associated virus approved for gene therapy, is placed into the identified focal region, these receptors may persist within the neurons and be modulated for years with medication. The medication dosage affects how strongly the receptor is activated, and therefore how much the neuron activity changes.

Since the activating medication is synthetic and highly selective, it affects only the designer receptor, thereby alleviating the side-effect problem.


While other papers with similar findings published around the same time as the CHOP-Penn paper, the research groups approached the problem from different angles.

“In our paper, we selectively expressed the designer receptor in the hippocampal excitatory neurons using a promoter element,” Dr. Anderson said. “We then turned them down; other researchers rebalanced the circuit by expressing a similar type of agent within inhibitory cells, then turned them up.”

Instead of competition, he sees the replication of scientific evidence as fortuitous, since it could lead more quickly to translatable solutions for clinical use.

“This wealth of evidence might eventually attract the interest of pharmaceutical or medical companies, with multiple groups showing the findings,” Dr. Anderson said. “And there is interest in using this chemogenetic approach for rebalancing circuitries for many different conditions, including epilepsy, which is Dr. Coulter’s area of expertise. So, further funding for additional understanding within the animal model is our current goal.”

Support from the Ethel Brown Foerderer Fund for Excellence was instrumental in getting the project moving forward, and the researchers aim to obtain additional funding to support their continued work.

Read more about the publication, co-authored with Julia Kahn, PhD, postdoctoral researcher in the CHOP Epilepsy Research Laboratory and the Penn Department of Neuroscience, and Russell Port, PhD, postdoctoral fellow at CHOP and in the Penn Department of Psychiatry, in Biological Psychiatry.