SickKids and U of T researchers demonstrate drug stimulation of neural stem cell repair may lead to promising impact on treatment of childhood brain injury in survivors of brain cancer

Through a novel study of metformin, a common drug used to treat type-2 diabetes, a team of researchers and clinicians from The Hospital for Sick Children (SickKids) and the University of Toronto (U of T) has shown that it could one day be possible to repair brain injury (caused by cancerous tumours as well as treatments for the tumours) using resident cells in the brain. 

“No one’s actually shown before that you can take a drug where there’s a known mechanism on endogenous stem cells and demonstrate that it’s even possible to induce brain growth and positive recovery,” says Dr. Donald Mabbott, Program Head and Senior Scientist, Neurosciences & Mental Health program, SickKids, and co-principal investigator of the study, published in Nature Medicine on July 27. 

Mabbott says metformin is a potential game changer in terms of how this type of childhood brain injury is treated. 

“We’re really moving from a model that says ‘let’s help children manage and compensate for their injury’, to ‘let’s actually treat the injury itself in an active way by harnessing the brain’s own capacity for repair,’” says Mabbott, who is also a professor of psychology at U of T. 

The published research showed that metformin has positive sex-dependent effects on neurogenesis, which is the process of growing neurons in the brain, while also demonstrating that it is safe to continue into a phase III clinical trial on humans. The human participants in this study were survivors of paediatric brain tumours who had received cranial radiation. 

“This study is so novel compared to most studies because it looked at both animal models and human participants. And we found these really consistent and interesting effects in terms of memory and brain recovery,” says co-principal investigator Dr. Cindi Morshead, Professor in the Donnelly Centre for Cellular and Biomolecular Research, Chair of the Division of Anatomy in the Department of Surgery and Medicine by Design-funded researcher, U of T.  

“This pre-clinical work in animal models will inform the design of the new study, currently in place, to help the brain recover from injury.” 

Morshead says she is not only excited by the promising results of the study, but also by the way its novel design encouraged clinical translation. 

“There’s a lot of history of pre-clinical models not working – drug therapies that go to the clinic and then don’t make it to the next phase. That can be devastating, for a lot of reasons. But I think, in us combining human and animal work, it really promoted the translation of this work into human testing,” she says. 

In a multi-disciplinary project, some members of the Nature Medicine study’s research team previously mapped brain development over time using single cell genomics, including Dr. Freda Miller, Senior Scientist, Neurosciences & Mental Health program, SickKids, and Morshead. This previous work provided insights into the circuits that control brain tissue growth and led to the identification of compounds that can stimulate resident stem cells to promote brain tissue repair, including metformin. 

"I am so excited by this paper since it describes a potential endogenous stem cell-based therapy for brain disorders that are currently untreatable,” says Miller. “And, just as importantly, the metformin story provides a classic example of why we need to support basic research and why working in collaborative teams is essential. The original finding that metformin recruits endogenous brain stem cells came from fundamental studies on how stem cells build the brain developmentally, and then it was moved forward to animal models and humans by highly interdisciplinary scientists and clinicians, like Drs. Mabbott and Morshead." 

This study presents important evidence that stimulating resident stem cells is a feasible approach for tissue repair in settings where regeneration does not readily occur. And, since metformin is an approved drug, the timeline for further clinical testing and regulatory approval could be accelerated. 

The results of the trials have informed a Phase III clinical trial for survivors of paediatric brain tumour treated with cranial radiation currently starting in 14 hospitals in Canada and Australia. 

In the lab, investigators found that metformin enhanced the recovery of endogenous neural precursor cells (NPCs) in the dentate gyrus (DG), a part of the brain that plays a critical role in learning and memory. But the results were sex-dependent; metformin was sufficient to rescue neurogenesis and behaviour in females, but not males. 

In addition to the lab study, a concurrent study with 24 children found that metformin is safe to use with no significant adverse events reported and is well tolerated by this population. 

Both Mabbott and Morshead say their work is motivated not just by the novel science of activating cells that are already resident in the brain to repair injury, but also by their desire to offer hope to a vulnerable population. 

“Working as a clinical psychologist with families for 20 years, it was really the families that motivated me – in fact, they challenged me,” says Mabbott. “My job was to tell parents that while their child was successfully treated for brain cancer there was a cost as their child will have learning problems, cognitive disabilities, and some will never live independently. It was a parent who said to me, ‘That’s not good enough, you have to figure out a way to help our kids recover better.’ That’s what motivated me to start to look at how to harness brain plasticity for repair.” 

Dr. Eric Bouffet is an investigator on the study and Director of the Brain Tumour program, Haematology/Oncology, and Senior Associate Scientist, SickKids.  

“Until recently, after-care programs were offering very little to children suffering the consequences of radiation treatment to their brains,” he says. “This study suggests that we can repair some of the damage associated with radiation to the brain and that children with brain tumours worldwide may potentially benefit from this discovery.” Bouffet is also a professor of paediatrics at U of T. 

Funders of this study include Brain Canada, Canadian Institutes of Health Research (CIHR), Ontario Institute of Regenerative Medicine, Stem Cell Network, U of T’s Medicine by Design, the Garron Family Cancer Centre and SickKids Foundation.