Experimental Treatments

Rett syndrome is a rare neurodevelopmental disorder that primarily affects girls. Patients experience behavioral and cognitive problems, as well as problems with sensation and movement.

Typical (classic) Rett syndrome is caused by mutations in the MECP2 gene. As a result of these mutations, the MECP2 protein is not made correctly. MECP2 is responsible for regulating when genes turn on and off during development. This results in the MECP2 protein, for which this gene encodes, not to function properly.

There is currently no cure for Rett syndrome, but there are treatments to manage the symptoms. Experimental treatments also are being developed by researchers.

Gene therapy

One approach to treating Rett syndrome is to use gene therapy to deliver a healthy copy of the MECP2 gene to the patient’s body. Gene therapy has its challenges, however, because too much MECP2 also can be very dangerous. Successful gene therapy will require exacting control of MECP2 gene activity.

AveXis is developing a gene therapy called AVXS-201 for treating Rett syndrome. Based on promising results from preclinical studies in mice and primates, Avexis plans to submit an investigational new drug application to the U.S. Food and Drug Administration (FDA) in 2019 in order to begin clinical trials testing the potential treatment in humans.

Modulation of MECP2 expression

The MECP2 gene is located on the X-chromosome. Women have two X-chromosomes and during development, one of the X-chromosomes is inactivated so that the right amount of proteins like MECP2 are made. One potential strategy to treat Rett syndrome is to activate the second healthy copy of the MECP2 gene to compensate for the loss of function of the mutated copy.

Alternatively, MECP2 protein could be delivered directly to the cells, or the intermediate between gene and protein (a temporary molecule called messenger RNA) could be repaired to allow the production of functioning MECP2 protein.

ANAVEX2-73 is a small molecule that activates a protein involved in correcting protein misfolding. Researchers think it may be able to treat Rett syndrome by helping MECP2 to fold correctly, compensating for the mutations. ANAVEX2-73 has received orphan drug designation from the FDA for treating Rett syndrome. A Phase 2 clinical trial (NCT03758924) assessing the safety, tolerability, and effectiveness of ANAVEX2-73 is currently recruiting patients in Alabama, Illinois, and Ohio.

Modulation of the immune system

Inflammation in the brain plays an important role in the development of Rett syndrome. Fingolimod is an immunomodulating medication approved for the treatment of multiple sclerosis (MS), and now is in Phase 1/2 clinical trials for the potential treatment of Rett syndrome.

Brain development and function

Trofinetide is a molecule derived from insulin-like growth factor 1 (IGF1). IGF-1 is essential for brain development and function, and researchers think that supplying an artificial form of IGF1 to patients may be able to compensate for the deficits in neuronal development seen in Rett syndrome. A Phase 2 clinical trial (NCT02715115) testing trofinetide has been completed and a Phase 3 clinical trial evaluating its effectiveness and safety is planned for 2019.

Modulation of neurotransmitters

Sarizotan is a molecule that binds to serotonin and dopamine receptors, activating them in the same way that serotonin and dopamine do. Serotonin and dopamine are neurotransmitters (cell-signaling molecules) in the brain and essential to its function. Serotonin levels are lower in the brain of patients with Rett syndrome, and Sarizotan is being investigated as a potential treatment to reduce breathing problems in patients. Essentially, Sarizotan would increase the nerve signals being sent by the brain, possibly compensating for the loss of nerve cells in Rett syndrome. A Phase 2/3 clinical trial (NCT02790034) testing sarizotan is ongoing.

Ketamine is a molecule that interacts with different receptors in the brain; it may reduce repetitive movements and respiratory problems. A Phase 2 clinical trial (NCT03633058) is recruiting patients in centers across the U.S. to assess the safety and tolerability of different doses of ketamine.

AMO-04 is a molecule that modulates the action of the neurotransmitter glutamate, vital to brain development and neuronal function. AMO-04 received orphan drug designation from the FDA in June 2018. AMO Pharma, the developer of the potential treatment, is partnering with Numedicus to continue its development.

Cannabidiol (CBD) is a compound isolated from cannabis with broad neurobehavioral effects without having a psychoactive action. A Phase 3 clinical trial (NCT03848832) evaluating the effectiveness of CBD in reducing the severity of symptoms in Rett syndrome is set to start in spring 2019 at locations in the U.S. and the United Kingdom.


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