Assessing the burden of MECP2 duplication syndrome on carers
MECP2 gene duplication syndrome is a progressive neurogenetic disorder which
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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.
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.
– Genetic studies: To accurately determine the type of duplication and adapt the dosage of ASO to each individual.
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.
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.
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.
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.
Un registre médical (ou épidémiologique) est une collection de données qui a pour but de répertorier les patients d’une maladie (âge, sexe, date des symptômes ou du diagnostic, sévérité de la maladie, localisation géographique…). Un registre permet de mieux suivre et caractériser une maladie : nombre de malades, caractéristiques épidémiologiques et médicales, évolution de la maladie chez les patients, etc…
Disposer d’un registre MECP2 est très important pour la recherche : la recherche clinique a besoin de connaître les patients atteints du syndrome de duplication du gène MECP2 pour recueillir le plus d’informations possible sur cette maladie rare.
Il existe actuellement plusieurs registres dans lesquels les personnes atteintes par ce syndrome peuvent être enregistrées. Ces registres permettent de faire progresser les connaissances sur le syndrome de duplication du gène MECP2 et de faire avancer la recherche d’un médicament.
Les chercheurs de l’institut de recherche neurologique au Texas (NRI) ont créé un registre international afin d’estimer de manière plus précise le nombre de personnes atteintes du syndrome. Outre d’établir la prévalence du syndrome, ce registre permet également de montrer l’importance du développement d’un médicament auprès des autorités de santé.
Même si vous ne souhaitez pas que votre enfant participe à des études cliniques, son inscription sur le registre est primordiale pour augmenter le nombre de malades répertoriés et donner plus de force aux actions de recherche bénéfiques à votre enfant et aux autres petits MECP2 du monde.
Pour inscrire votre enfant sur le registre, munissez-vous du rapport du généticien confirmant le diagnostic, et remplissez le formulaire de consentement. Celui-ci est actuellement disponible en 5 langues : français, anglais, allemand, espagnol et japonais. A la suite de l’évaluation de votre demande de participation, vous recevrez une confirmation de votre inscription au registre.
Afin d’augmenter les connaissances sur les déficiences intellectuelles liées aux mutations sur le chromosome X, l’équipe de Genida a mis en place un registre international.
Un questionnaire est à remplir par les parents ou professionnels de santé impliqués dans la prise en charge des patients. Il permet d’identifier avec plus de précision les symptômes du syndrome ainsi que d’établir l’âge moyen d’apparition de ces symptômes.
L’équipe de l’institut du Telethon Kids (Australie) s’efforce de mieux caractériser les caractéristiques cliniques et l’histoire naturelle de la duplication du gène MECP2, encore trop peu connues.
Pour y parvenir, les chercheurs ont lancé la base de données internationale sur le syndrome (MDBase). Nous vous invitons à participer à cette initiative passionnante dont l’objectif est de recueillir des informations sur la santé et le bien-être des enfants et des adultes atteints de cette maladie.
Ces informations indispensables aideront les chercheurs du Telethon Kids à comprendre les changements qui peuvent survenir avec l’âge et permettront de mieux orienter les discussions entre parents et professionnels de la santé.
Les scientifiques présentent leurs travaux de recherche sur le syndrome de duplication du gène MECP2. Retrouvez les vidéos ici.
Les avancées de chaque projet de recherche sur le syndrome de duplication du gène MECP2 sont publiées périodiquement par les chercheurs. Retrouvez les articles ici.
MECP2 gene duplication syndrome is a progressive neurogenetic disorder which
Shao et al. from Prof. Zoghbi's group (Baylor College of Medicine, Texas,
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