Gli1 – a brand new drug target for demyelinating disorders?

The elucidation of a pathway involved in remyelination has yielded a novel potential target in the treatment of neurodegenerative diseases such as multiple sclerosis (MS).

MS is an autoimmune neurological condition affecting around 100,000 people in the UK alone and is characterized by demyelination – damage to the insulating myelin sheath of neurons. MS causes a wide range of symptoms depending on the location of the damage in the CNS and can include fatigue, blurred vision, mobility problems and muscle weakness, often drastically decreasing quality of life. Many current treatments target the immune system in an attempt to slow the disease, but drugs that have the ability to combat demyelination itself have so far remained elusive. Now, a series of elegant experiments by researchers at NYU Neuroscience Institute ( appears to have shed some light on the process of endogenous remyelination, which has important implications for the treatment of demyelinating disorders.

In adult human and mouse brains, remyelination is performed by two cell types: oligodendrocyte progenitor cells (OPCs) and neural stem cells (NSCs). Little is known about how NSCs in particular are recruited to lesion sites for their ultimate differentiation into oligodendrocytes, but a likely candidate involved in their regulation is sonic hedgehog (Shh), a morphogen with important roles in CNS development and NSC maintenance. Specifically it is Gli1, a transcription factor downstream in the Shh signaling pathway that has been the focus of this research.

Studying mice that express green fluorescent protein (GFP) in all Gli1-expressing cells, the researchers were first able to identify that Gli1+ NSCs have a prominent role in remyelination, and continue to generate glial cells for a prolonged period of time after demyelination. Using cuprizone to stimulate selective demyelination in the corpus callosum (CC), it was observed that GFP-expressing cells were recruited to damaged areas after six weeks, which then differentiated exclusively into glial cells – primarily oligodendroglia – two weeks after cuprizone was removed. Further, the numbers of GFP+ cells – comprising of OPCs, oligodendrocytes and astrocytes – continued to increase ten weeks after cuprizone removal.

Gli1-expressing cells are recruited to sites of demyelination. Markers of oligodendrocytes (CC1), oligodendrocyte progenitors (PDGFR-alpha) and astrocytes (GFAP) are observed in increasing amounts after cessation of cuprizone.

The relationship between Shh and Gli1 was then probed by further fate-mapping experiments of Gli1+ cells in mice, and it was found that Shh-responsive NSCs are recruited to demyelinated lesions in the CC where they downregulate Gli1 and differentiate into mature oligodendrocytes. Based on this finding, the question was raised as to whether inhibition of Shh signaling might enhance remyelination. To this end, the researchers fate-mapped NSCs in Gli1-null mice and indeed found an increase in GFP+ cells in the CC and an overall increase in myelin, but interestingly targeted ablation of Shh signaling did not increase GFP+ cells in the CC, indicating Gli1 has a specialized role in Shh signaling and myelination.

The next logical step, then, was to attempt targeted inhibition of Gli1 as a novel means to promote remyelination. This was done using the experimental drug GANT61, a small molecule inhibitor of Gli1, originally identified from a National Cancer Institute of chemical compounds as a potential therapy for brain and basal cell cancers.

Excitingly, it was found that GANT61 strongly promoted remyelination by enhancing the recruitment and differentiation of Shh-responsive NSCs into oligodendrocytes at demyelinated lesions. Specifically, mice receiving GANT61 during and after cuprizone treatment had significantly greater GFP+ cells, a significant amount of which were oligodendrocytes, resulting in more myelin present in the CC of treated mice compared to control-treated mice. In addition, when GANT61 was tested in a relapsing-remitting model of experimental autoimmune encephalitis (RR-EAE), a model of inflammatory demyelination and remyelination, they observed enhanced levels of remyelination and neuroprotection.

Mice given GANT61 had an approx. sevenfold increase in GFP-labeled cells in the CC (a) and a significant increase in the number of mature oligodendrocytes (b). Mice fed cuprizone then treated with either vehicle or GANT61 showed significantly higher fluorescence levels in GANT61-treated mice (c).

The implications of these findings are twofold: we now have an improved understanding of the mechanisms underlying myelination, and a starting point for the next generation of demyelination-targeting MS drugs. With an increasingly unmet need for well-tolerated MS therapies that do not target the immune system, it would not be surprising if this paves the way for numerous novel drug discovery avenues.
Blog written by Chloe Koulouris

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