MECP2 Family Conference

Dear MECP2 Duplication Syndrome Community,

We have just completed another successful family conference. Families from North America, South America, Europe and Australia came together and listened to the most recent updates from scientists working on MDS and physicians taking care of individuals with MDS. We thank all of them for their participation despite the challenges from COVID. You can access the videos in the following links:

• https://bcmedumy.sharepoint.com/:v:/g/personal/231165_bcm_edu/EWLasZT7vnRFrE9sBL60yJsB6rNc2CiijwCxpCjmdKsgWw?e=Tkh6Ih
• https://bcmedu-my.sharepoint.com/personal/231165_bcm_edu/_layouts/15/stream.aspx?id=%2Fpersonal%2F231165%5Fbcm%5Fedu%2FDocuments%2FMECP2%5FSAT%5F092422%2Emp4&ga=1

We would like to summarize the key takeaways from the conference for the entire MDS community.

• Ionis Pharmaceuticals intends to launch an observational or Natural History Study to learn more about the natural disease progression of MDS in 2023. The natural history study is expected to be conducted in the United States and will be limited in size to include approximately 40 individuals with MDS. It is anticipated that the natural history study will be comprise of quarterly visits in the 1st year followed by semi-annual visits in the 2nd year. Ionis Pharmaceuticals intend to interact with FDA in 2023. However, it is important to clarify that this is distinct from a submission or approval of an IND. Further announcements will be made by Ionis Pharmaceuticals.
• Drs. Davut Pehlivan and Sameer Bajikar talked about the genomic studies. Genomic studies continue to reveal that different types of duplications (i.e. simple – complex – triplication) and measurements of the level of the MeCP2 protein will guide the ASO dosing. Recruitment for the genetic studies is ongoing and you can participate from anywhere in the world.
• Dr. Mirjana Maletic-Savatic talked about the biomarker studies. Biomarker discovery studies are on target and we have a handful candidate biomarkers that differ between MDS, Rett and healthy individuals. Our aim is to narrow down the list of candidate biomarkers through the NHS study and identify one or two strong biomarkers that can reflect disease severity and response to ASO.
• Drs. Sarika Peters and Jeff Neul talked about outcome measure development. There will be a multicenter clinical impression scale development effort with the goal of using this scale in the upcoming clinical trial.
• Dr. Zhenya Ivakine reported a newly developed mouse model that expresses both MECP2 and IRAK1 with the goal of a better animal model to be used in MDS studies. He also provided an update on the CRISPR/Cas9 based genome editing in MDS. Although the results are encouraging, further laboratory studies are needed prior to proceeding to human studies.
• Dr. Ashley Anderson presented the preliminary results from a screen designed to find regulators of MeCP2. Inhibiting such regulators has the potential to lead to new treatments but these studies are in the early phase and need further work.
• We also heard from the clinical experts about common problems (e.g. gastrointestinal, epilepsy, frequent infections) in MDS. Given that epilepsy is the major problem causing regression in MDS and there is no clear seizure medication guidance, we plan to launch a large extensive survey study to identify the most beneficial approach for seizure management in MDS.

Huda Zoghbi, MD                                    Davut Pehlivan, MD                                     Bernhard Suter, MD