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New Treatment for Rett Syndrome Suggests the Disorder is Reversible

DNA Molecule

Rett syndrome is a very rare autistic-like disorder that is not detectable at birth (in most cases signs of it develop at 6 to 18 months of age) and occurs in about 1 in 10,000 to 1 in 15,000 females, as 90% of the children who have Rett syndrome are girls. Most boys diagnosed with this disorder die within the first 2 years due to a severe encephalopathy. Mostly girls are affected because they have two X chromosomes, and the disorder is caused by mutations in a gene on the X chromosome called MECP2.

Rett syndrome is considered as one of the most devastating and deadliest neurological disorders and current therapy relies only on treatment of the symptoms. Children diagnosed with this disease typically have no communicating skills, most of the affected individuals can’t walk, and some of the other very common problems that occur are growth problems, scoliosis, constipation, and brain decline.

Professor Nicholas Tonks at the Cold Spring Harbor Laboratory and his team developed the first drug, codenamed CPT157633, that shows promise at reversing Rett syndrome symptoms. First studies have been done on mice and X-ray crystallography at atomic level shows that the drug binds to its target, the enzyme PTP1B that was discovered after 25 years of research, which helps in regulating key metabolic and signaling pathways.

Rett Syndrome

Atomic-level model shows one of the experimental compounds named CPT157633 in mice modeling Rett syndrome interacts with the protein tyrosine phosphatase PTP1B. The result is inhibition of the enzyme and promotion of BDNF-TRKB signaling. (Image Credits: Tonks Lab/CSHL.edu)

The PTP1B group of enzymes is responsible for growth and development and Tonks team found 105 different PTP1B enzymes. One of these PTP1B enzymes was found to be elevated in mice that had the chromosome defect causing Rett syndrome, and Tonks’ team developed a few drugs that inhibit the function of this PTP1B enzyme that is associated with the MECP2 chromosome.

These drugs extended lifespan in male mice by as much as 90 days; female mice showed reversal of symptoms with at least 25% efficiency making this the first drug therapy that has the potential to reverse Rett syndrome at atomic-level, showing a lot of promise to further test it’s effects and hopefully in a very near future help the children coping with this disorder to get the best possible treatment.

The findings have been published in The Journal of Clinical Investigation titled “PTP1B inhibition suggests a therapeutic strategy for Rett syndrome”.

About the author

Warren Simons

  • Mel Lancaster

    While this is a promising therapeutic avenue, it should be noted that it is not the first drug that shows promise in reversing the symptoms of Rett Syndrome. Trofinetide (NNZ 2566) developed by Neuren Pharmaceuticals has already had a successful phase II trial, achieved Fast Track and Orphan Drug Status and is moving forward with guidance from the FDA.