Rett syndrome is a rare genetic disease characterized by behavioral, cognitive, emotional, sensory, motor, and autonomic problems.

There is currently no cure for Rett syndrome, and treatments focus on the management of symptoms and improvement of patients’ quality of life. Researchers are also investigating approaches to interfere with the course of the disease.

Management of symptoms

Research on disease-modifying therapies

Rett syndrome is caused by mutations in the MECP2 gene. This results in the MECP2 protein, for which this gene encodes, not to function properly.

One treatment approach is to use gene therapy to deliver a healthy copy of the MECP2 gene to the patient’s body. Following this strategy, Avexis developed AVXS-201. 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 this year in order be able to start clinical trials testing the potential treatment in humans.

However, gene therapy for Rett syndrome is challenging because too much MECP2 protein can be harmful to the cell. Gene therapy is, therefore, still in the early stages of development.

There are other treatment approaches that are being investigated for Rett syndrome:

Fingolimod is an immunomodulating medication approved for the treatment of multiple sclerosis (MS). For the treatment of Rett syndrome, it is in Phase 1/2 clinical trials.

Trofinetide is a molecule derived from insulin-like growth factor 1 (IGF1), a naturally occurring protein in the brain. IGF-1 is essential for brain development and function. A Phase 2 clinical trial (NCT02715115) testing trofinetide has been completed and a Phase 3 clinical trial evaluating its efficacy and safety is planned for the second half of 2019.

Sarizotan is a molecule that binds to serotonin and dopamine receptors. Serotonin and dopamine are two neurotransmitters, or signaling molecules, in the brain essential to its function. By binding to these receptors, sarizotan imitates some of the functions of serotonin and dopamine. Sarizotan is being investigated as a potential treatment to reduce breathing problems in Rett syndrome patients. A Phase 2/3 clinical trial (NCT02790034) testing sarizotan is currently 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 around the U.S. The trial will 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 Pharma received orphan drug designation for AMO-04 in June 2018.

ANAVEX2-73 is a small molecule that can modulate cellular processes that are relevant for neurological function. ANAVEX2-73 has received orphan drug designation from the FDA for the treatment of Rett syndrome. A Phase 2 clinical trial (NCT03758924) assessing the safety, tolerability, and efficacy of ANAVEX2-73 is currently recruiting patients in Alabama and Ohio.

Cannabidiol (CBD) is a compound isolated from cannabis with broad neurobehavioral effects but without psychoactive action. A Phase 3 clinical trial (NCT03848832) evaluating the efficacy of CBD in reducing the severity of symptoms in Rett syndrome is set to start this month across the U.S. and in the U.K.

Other approaches that aim to restore MECP2 function are being investigated in preclinical studies.

One strategy is to activate the second healthy copy of the MECP2 gene located on the second X chromosome in female patients to compensate for the loss of function of the mutated copy. (Females have two X chromosomes; each contains one copy of the MECP2 gene, of which one copy is mutated in Rett syndrome patients.)

A further approach is to deliver the MECP2 protein directly into the cells.

Another approach aims to repair the MECP2 mRNA. mRNA serves as an intermediary between a gene and a protein that fulfills function in the cell.


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