Therapeutic for Rett syndrome shows success in preclinical mouse models

Scientists at IDIBELL have reported preclinical success as Mecp2 deficiency in a mouse model is partially rescued following treatment with a novel drug candidate.

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May 17, 2018

A recent study published in Cell Reports describes the successful preclinical trials for a novel drug candidate to treat Rett syndrome, which was demonstrated to be able to both reduce symptoms and activate the characteristic dormant neurons.

Loss-of-function mutations in the methyl CpG-binding protein 2 (MeCP2) gene in humans are responsible for over 95% of cases of Rett syndrome, characterized by growth failure, gastrointestinal problems, seizures, and respiratory and cardiac abnormalities. Researchers at the Institut d’Investigació Biomédica de Bellvitge (IDIBELL; Barcelona, Spain) have tested the compound SB216763, known to inhibit the neuroinflammatory protein glycogen synthase kinase-3B, in Mecp2-knockout mice.

"We knew for some years [sic] that the brains of Rett syndrome girls were inflamed, so we decided to test whether a drug that inhibits a central neuroinflammatory protein called glycogen synthase kinase-3B (GSK3B) could reverse part of the symptoms. As with any experimental treatment, we started with a preclinical model of the disease, studying it in mice that have the same Mecp2 deficiency as in human Rett syndrome," commented lead author Manel Esteller, Director of the Epigenetics and Cancer Biology Program at IDIBELL.

Rett syndrome, after Down syndrome, is the second most frequent cause of intellectual disability in women. There is currently no specific pharmacological treatment and efforts are focused on trying to control some of the more severe symptoms of the disease, namely, epileptic and respiratory crises.

"The results have been very promising; agent SB216763 has been able to lengthen the life of the animals, significantly reducing tremors, breathing difficulties and mobility limitations. But what is really remarkable is that the inhibition of GSK3B also causes an "awakening" of the sleeping neurons of the syndrome: these brain cells are now beginning to regain contact between them and communication between neuronal synapses increases,” explains Esteller.

"Our findings provide a new way of improving the quality of life of these patients and now it is the neurologists’ job to demonstrate their applicability in patients with Rett Syndrome. In any case, we have to be aware that the mutation in the MeCP2 gene is still there, and only by correcting it would we arrive at a definitive treatment of the disease."

Jorge-Torres OC, Szczesna K, Roa L et al. Inhibition of Gsk3b reduces Nfkb1 signaling and rescues synaptic activity to improve Rett syndrome phenotype in Mecp2-knockout mice. Cell Rep. 23, 1665–1677 (2018);

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Jasmine Harris

Digital Editor, Future Science Group

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