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Cambridge Stem Cell Institute

Uncovering new therapeutic interventions for Multiple Sclerosis

Results from a Phase 2 trial, based on underpinning research from the Franklin lab have shown that remyelination is possible in humans. These results are being built on in a new clinical trial funded by the MS Society, based on further research from the Franklin group, involving the diabetes drug metformin and the antihistamine clemastine.

Remyelination is the process by which the body regenerates myelin, the fatty sheath that surrounds our nerves, and which is lost in multiple sclerosis (MS). Results from a Phase 2a trial, studying the effects of the RXR agonist bexarotene has shown in vision tests and MRI scans that myelin repair had taken place. This trial, led by Professor Alasdair Coles (Department of Clinical Neurosciences), was based on research from the Franklin lab at the Cambridge Stem Cell Institute. This research, published in Nature Neuroscience in 2011, showed that the retinoid X receptor pathway is a positive regulator of adult CNS progenitor cell differentiation and a key player in the age-related decline in remyelination. The CCMR One Trial showed that remyelination is possible and, although bexarotene will not enter a Phase 3 trial because of the drugs side effects, the lessons learned from this study will be taken forward to new trials.

The MS Society have announced that they will fund a new clinical trial which builds on these results and will test the diabetes drug metformin in combination with clemastine (an antihistamine). This will build on research published in October 2019 in Cell Stem Cell by the Franklin group which showed that metformin, a common diabetes drug, could hold the key to stopping disease progression in multiple sclerosis (MS). This study, carried out in rats, showed that treatment with metformin reversed the effects of ageing on adult brain stem cells, enabling them to engage effectively in the process of remyelination. These findings will now be taken forward in a new Phase 2 clinical trial in 50 people with relapsing MS. This trial will also be led by Professor Alasdair Coles at Addenbrooke’s Hospital.

Professor Robin Franklin said: “Metformin is one of the most exciting developments in myelin regeneration we have ever seen. Our findings last year shed light on why cells lose their ability to regenerate myelin, and how this process might be reversed. We’re very proud to have done this work and thrilled to see our discovery taken forward so quickly.”

Publication details:

Huang JK, Jarjour AA, Nait Oumesmar B, Kerninon C, Williams A, Krezel W, Kagechika H, Bauer J, Zhao C, Baron-Van Evercooren A, Chambon P, Ffrench-Constant C, Franklin RJM. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nature Neuroscience. 2011 Jan;14(1):45-53. doi: 10.1038/nn.2702.

Neumann B, Baror R, Zhao C, Segel M, Dietmann S, Rawji KS, Foerster S, McClain CR, Chalut K, van Wijngaarden P, Franklin RJM. Metformin Restores CNS Remyelination Capacity by Rejuvenating Aged Stem Cells. Cell Stem Cell. 2019 Oct 3;25(4):473-485.e8. doi: 10.1016/j.stem.2019.08.015.