Genetically altering proteins could inform treatment development for children with epilepsy

Researchers at The Hospital for Sick Children (SickKids) have uncovered how a molecular mechanism could inform new therapeutic targets for treatment-resistance epilepsy, autism spectrum disorder (ASD) and other neurodevelopmental conditions.  

Neurodevelopmental conditions such as epilepsy affect as many as one in 100 Canadians. Many strategies exist to try to control seizures, including medication and neurosurgery, but these approaches are not always successful and, in the case of neurosurgery, can be invasive.

In a study published in Cell Reports, researchers led by Dr. Yun Li, a Scientist in the Developmental & Stem Cell Biology program, show that by genetically altering specific proteins, they may be able to reduce the impact of certain neurological conditions, including epilepsy, and potentially improve outcomes for patients. 

 “Our research findings could change the way we approach managing neurodevelopmental conditions such as treatment-resistant epilepsy,” Li says.  

Stopping excessive cell growth in its tracks 

PTEN is an important gene in the development and function of the brain which, when varied or missing, increases abnormal cell growth which can contribute to neurological conditions associated with abnormal brain activity, like epilepsy.  

There are two protein complexes that regulate brain cell growth and electrical activity: mTORC1 and mTORC2. Previously, scientists thought these two complexes had distinct roles in controlling different aspects of cell growth and electrical activity, but Li’s team wanted to dive in further.

In their research, the lab used neurons derived from human stem cells and tissues that mimic brain function. First author Dr. Navroop Dhaliwal, a postdoctoral fellow in Li’s lab, developed a human stem cell tool that allowed the research team to conduct pharmaceutical and genetic screens in edited human neurons more rapidly and efficiently. Together with co-first author Octavia Weng, a PhD student in Li’s lab, the team genetically altered just one of the complexes in combination with PTEN gene variation.

Surprisingly, they found that these two complexes function together and that the genetic intervention of either mTORC1 or mTORC2 could fully restore the cell growth and electrical alterations caused by PTEN variation.

“Previous pre-clinical models showed that both mTOR complexes need to be inhibited to relieve symptoms, while our current study is the first in human brain cells to show that genetically modifying just one complex can be highly beneficial,” Li says. “These molecular targets could be used to tailor future treatment options, and ultimately benefit patients.” 

Side-stepping the blood brain barrier 

While neurodevelopmental conditions are thought to have both genetic and environmental causes, how these factors impact the human brain is not well known, highlighting the importance of using human cells in research. To meet this need, Li’s lab mimics genetic variations using human brain cells inside of a petri dish. In addition to providing human-specific insights, this strategy allows scientists to sidestep the blood brain barrier: a membrane encasing the brain that keeps water-soluble molecules from entering, making it difficult to assess the impact of potentially therapeutic drugs on brain function. 

“Using this approach, we are able to investigate the impact of external factors directly on human brain cells,” explains Li. “We hope this technique will allow us to identify more precise drug targets for children with these conditions and reduce the need for invasive surgeries.”  

Future research from Li’s lab will explore the implications of these findings on other neurodevelopmental conditions characterized by the same protein pathway, such as tuberous sclerosis and fragile X syndrome.  

This study was supported by the University of Toronto’s Medicine by Design initiative, the Canada First Research Excellence Fund, the Canada Research Chairs program, the Simons Foundation, the Canadian Institutes of Health Research (CIHR), the Sharon Francis Foundation, Can-GARD, the Stem Cell Network, Brain Canada, the Brain and Behavior Foundation, the McLaughlin Centre, Epilepsy Canada, the Scottish Rite Charitable Foundation of Canada, Restracomp, the Ontario Graduate Scholarship and the Garry Hurvitz Centre for Brain & Mental Health.