Approaches to Repairing Damaged White Matter in Children and Young Adults with MS
- While existing MS therapies effectively target the inflammatory factors related to the disease, there is a need for effective treatments that can reverse the progressive nature of the disease by promoting repair of white matter and reducing disability.
- Preclinical evidence shows that metformin, a widely-used and safe drug typically prescribed to treat type II diabetes, enhances brain repair (white matter) in animal models and also in youth following radiation-induced brain injury.
- Researchers aim to translate preclinical findings by conducting a pilot feasibility trial to investigate metformin in children and young adults with MS as a therapeutic with potential to enhance repair in people living with MS.
- Dr. Ann Yeh, The Hospital for Sick Children, University of Toronto (Lead Investigator)
- Dr. Jiwon Oh, St. Michael’s Hospital, University of Toronto
- Dr. Wolfram Tetzlaff, University of British Columbia
- Dr. Paul Frankland, The Hospital for Sick Children, University of Toronto
- Dr. Jing Wang, Ottawa Hospital Research Institute
- Dr. Cindi Morshead, Toronto Rehabilitation Institute, University Health Network, University of Toronto
- Dr. David Kaplan, The Hospital for Sick Children, University of Toronto
- Dr. Freda Miller, The Hospital for Sick Children, University of Toronto
- Dr. Douglas Munoz, Queen’s University
- Dr. Donald Mabbott, University of Toronto
Damage to white matter in the brain occurs in people living with multiple sclerosis (MS), resulting in sensory, motor, and cognitive impairment. Current therapies for MS mostly target the inflammatory factors related to the disease, but do not reverse the progressive nature of the disease. Therefore, there is a need for effective therapies that can promote white matter repair in the brain and reduce disability in people living with MS.
Dr. Ann Yeh and colleagues have shown that the widely-used and safe drug, metformin enhances the generation of oligodendrocytes and neurons from neural precursor cells. Oligodendrocytes are key cells in the body that produce myelin – the protective coating surrounding nerve fibres. In MS, the immune system attacks myelin, which often becomes damaged causing inflammation, and this can disrupt the body’s ability to properly transmit nerve signals. In animal models, metformin has been shown to promote motor and cognitive recovery by enhancing oligodendrocyte regeneration and promoting remyelination. They also found that use of metformin is associated with white matter repair in children following radiation-induced white matter brain injury.
As part of this research study, the team will provide further evidence that metformin enhances the genesis of oligodendrocytes and encourages their development into mature oligodendrocytes in preclinical rodent models of demyelination. Using these tools, the team also aims to identify additional novel strategies for increasing the generation of oligodendrocytes from neural precursor cells. It is believed that the most efficacious repair strategies will require a combination of treatment strategies.
Dr. Ann Yeh and team will translate the preclinical findings from animal and human studies to the clinic by conducting a pilot feasibility trial to investigate metformin and whether it can promote white matter repair in children and young adults with MS. The feasibility study (a Phase I/II) is a multiple baseline double blind randomized controlled trial, evaluating 3-, 6- or 9-months of treatment with metformin in a 2-step dose escalation. The pilot feasibility trial will recruit 30 participants between the ages of 10 to 25 years of age who have a diagnosis of MS. The study will assess primary and secondary outcomes: feasibility, tolerability, patient satisfaction, visual system and visual function metrics, functional metrics (e.g. EDSS, MEG, and neuropsychological and patient-reported outcomes) and structural brain metrics (e.g. white matter structure) among other measures.
Potential Impact: This feasibility trial is an essential step towards providing preliminary evidence in support of a larger-scale randomized controlled trial for white matter repair. Metformin is an inexpensive generic drug, therefore if shown to be effective, the re-purposing this drug to treat MS would provide a low-cost strategy for people living with MS. Overall, this project aims to advance treatment and care for people affected by MS by providing a novel pharmacological intervention that promotes repair.
Project Status: In Progress
*This research is funded in partnership with Stem Cell Network (SCN), Ontario Institute for Regenerative Medicine (OIRM) and MS Society of Canada. MS Society of Canada is providing $400,000, SCN is providing $400,000 and OIRM is providing $200,000 in support of this research.
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