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Current projects

Due to the duplication of the MECP2 gene, the MeCP2 protein is produced in excess in all cells of the body. The disorders associated with MECP2 duplication syndrome are due to the excess of this protein in the brain. 

Research groups around the globe are working to better understand MECP2 duplication syndrome (MDS) and develop innovative technologies for its cure. Efforts to treat MDS include reducing levels of the MECP2 protein through DNA editing (CRISPR Cas9), MECP2 gene expression silencing (SiRNA, ASO, and CRISPR Cas13), or drug repurposing.

Antisense Oligonucleotides,  Prof. Zoghbi (Houston, Texas)


In collaboration with the pharmaceutical company IONIS Pharmaceutical, a team of Prof. Zoghbi’s, led by Dr. Davut Pehlivan has developed a drug, belonging to the “Antisense” family (ASO). This molecule, under clinical evaluation, specifically reduces the level of MeCP2 protein in brain cells.

The team led by Zoghbi and Pehlivan has developed a mouse model in which the mouse manifests the typical symptoms observed in children with MECP2 duplication syndrome.

In 2015, the team demonstrated that it is possible to reverse the symptoms of the syndrome in this mouse model. The normalization of the MeCP2 protein concentration after administration of ASO allowed the improvement of all the symptoms characteristic of the syndrome in mice, even when starting the treatment at an advanced age.

In 2021, in order to prepare for clinical studies, Prof. Zoghbi’s team created a mouse model that, like children with MDS, have 2 copies of the human MECP2 gene. This new mouse model confirmed the results previously obtained with ASO. These results give hope to be able to reverse the symptoms also in humans. To do this, it is necessary to deliver ASOs effectively to the brain and to safely control the level of the MeCP2 protein.

Researchers are currently working on a new method of administering ASOs by intrathecal injection that allows a much wider distribution of the drug in the brain. This technique has so far proven effective in human infants with other diseases.

Finally, because it is critical to have the correct level of MeCP2 protein in the brain, the team must accurately determine the dose of ASO needed for each patient. For this reason, the following clinical studies are underway before we can intervene in humans:

– Biomarker evaluation: MeCP2 regulates other proteins that affect the body. An overdose of MeCP2 causes a change in these proteins. By identifying biomarkers/proteins that are regulated by MeCP2, researchers will be able to quickly assess the effectiveness of the administered ASO.

– Clinical Severity: Establish a link between the type of duplication and the resulting symptoms over time in order to evaluate the effectiveness of the treatment in relation to the patient’s symptoms. ion de ces protéines.

– Genetic studies: To accurately determine the type of duplication and adapt the dosage of ASO to each individual.

Drug Repositioning, Dr. Pehlivan (Houston, Texas)

Davut Pehlivan

The objective of this project is to identify a drug, already on the market, capable of reducing the level of this protein using two approaches:

-Testing a maximum of drugs currently approved by the FDA (US Food and Drug Administration) on other therapeutic targets to see if they have an effect on the MeCP2 protein (e.g. degradation, inactivation etc…). The advantage of this method is that the clinical development of the drug will be greatly accelerated, since its safety profile is validated.

– Test each gene in the genome to identify those that regulate the expression of the MeCP2 protein. Once these regulators are identified, researchers will work to find drugs, already on the market, to inhibit them. So far, several regulators of the MECP2 gene have been identified. A drug that acts on one of these regulators has already improved some symptoms in MDS mice.

Dr. Pehlivan’s team continues to identify new regulators and evaluate drugs to find those that will offer the greatest efficacy while limiting possible side effects.

SiRNA, Prof. Khvorova (Boston, Massachusetts)

Prof. Anastasia Khvorova is a pioneer in the field of oligonucleotides and is a member of UMASS in Boston, Massachusetts, which includes many experts in RNA, including 2006 Nobel Laureate in Medicine Craig Mello.

Prof. Khvorova’s team used small RNA-interfering oligonucleotides (SiRNAs) to prevent the translation of targeted proteins by binding to their messenger RNA and promoting its degradation. Molecular scissors are guided by the SiRNA which vary the MeCP2 messenger RNA to destroy it, thereby reducing the level of MeCP2 protein in the cell.

The model developed by Prof. Khvorova shows a robust distribution of SiRNA throughout the brain and spinal cord. Her approach suggests that a treatment could be administered once a year to keep the level of MeCP2 protein constant.

CRISPR CAS9, Dr. COHN (Toronto, Canada)

Dr. Cohn and his team are proposing a strategy for genome editing. This project uses the genome editing technique known as CRISR-CAS9, which won the 2020 Nobel Prize in Chemistry for Emmanuelle Charpentier and Jennifer Doudna.

This technique consists in “correcting” the DNA directly, leading in the case of MECP2 duplication syndrome, to the definitive and specific deletion of the duplicated area. Only one copy of the MECP2 gene remains in each of the targeted cells, which results in the normalization of the MeCP2 protein concentration.

A mouse model to test this therapeutic strategy has already been developed and is ready for use. Dr. Dr. Cohn and his team have already demonstrated that this technique works on fibroblasts (skin cells) from patients with MECP2 duplication syndrome.

Using the same approach, the research group also observed an improvement in symptoms in a mouse model that developed muscular distrophy Duchenne.

The route of administration of this type of new treatment is currently being evaluated.

CRISPR CAS13, HuidaGene Therapeutics (Shanghai, China)

HuidaGene Therapeutics is a biotechnology company based in Shanghai, focusing on discovering, engineering, and developing novel CRISPR-based medicines. HuidaGene has developed HG204, an adeno-associated viral (AAV) vector delivering a CRISPR-Cas13 complex into cells. Specially designed for MECP2 duplication syndrome, HG204 aims to regulate the overproduction of the MeCP2 protein levels by inducing the degradation of overexpressed MECP2 RNA. This innovative drug candidate holds the potential to cure MDS through a single administration. 

Preclinical studies using HG204 in a humanized MDS mouse model demonstrated a significant reduction of MeCP2 protein and reversal of the symptoms. 

HuidaGene is in the process of finalizing pre-clinical studies with HG204 and getting ready for a clinical trial for patients in China, scheduled to begin in mid-2024. If this trial is successful, HuidaGene will plan clinical trials in other countries such as the USA and Europe in 2025-2026. 

On the 31st of October 2023, the FDA (Food and Drug Administration, the health authority of the US) granted both Rare Pediatric Disease and Orphan Drug Designations to HG204. This regulatory designations are a first step towards a clinical trial outside of China and shall enable an accelerated review of the dossier upon registration of the drug.


A medical (or epidemiological) registry is a collection of data that allows listing and description of patients with a specific disease (age, sex, date of symptoms or diagnosis, severity of the disease, geographical location, etc.). A registry allows better monitoring and characterization of a disease: number of patients, epidemiological and medical characteristics, evolution of the disease in patients, etc.

Having a MECP2 registry is very important for research: clinical research needs to know the patients with MECP2 duplication syndrome in order to gather as much information as possible on this rare disease.

There are currently several registries in which people with this syndrome can be registered. These registries help to advance knowledge about MECP2 and to advance the search for a drug.

Neurological Research Institute (NRI) registry

Researchers at the Neurological Research Institute (NRI) in Texas have created an international registry to more accurately estimate the number of people with the syndrome. In addition to establishing the prevalence of the syndrome, this will also help demonstrate the importance of drug development to health authorities.

Even if you do not want your affected family member to participate in clinical studies, your enrollment in the registry is important to your family member and to all the other children with MECP2 duplication syndrome in the world.

To enroll your affected family member in the registry, please have the geneticist’s report confirming the diagnosis, and fill out the consent form. The consent form is currently available in 5 languages: English, French, German, Spanish and Japanese. After an evaluation of your application, you will receive a confirmation of your inclusion in the registry.

In order to increase knowledge about intellectual disabilities related to mutations on the X chromosome, the Genida team has set up an international registry.

This registry is a questionnaire to be filled out by parents or healthcare professionals involved in the care of patients. It allows for a more accurate identification of the symptoms of the syndrome as well as the average age of onset of these symptoms.

InterRett registry

The Telethon Kids Institute (Australia) team is working to better characterize the clinical features and natural history of MECP2 gene duplication, which is still not well known.

To achieve this, the researchers have launched the international database on the syndrome (MDBase). We invite you to participate in this exciting initiative, which aims to collect information about the health and well-being of children and adults with this disease.

This much-needed information will help Telethon Kids researchers understand the changes that can occur with age and would allow to better focus discussions between parents and health care professionals.

Expert webinars

Scientists present their research on MECP2 gene duplication syndrome. Find the videos here.


The progress of each research project on MECP2 gene duplication syndrome is published periodically by the researchers. Find the articles here.

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