Summary of the American Family Conference 2022

The biannual family conference was held in Houston (Texas, USA) from 23 to 24 September 2022. It was organised by Professor Huda Zoghbi of the Neurological Research Institute (NRI, Houston, Texas). The programme was packed and included presentations on scientific advances in the syndrome.

David Covini, vice-president of the French association "Les petits Mec P2", president of the Austrian association "Lasst uns MDs heilen" and member of the scientific committees of both associations, visited the site. He met the families present, the active members of the American associations and the researchers.

David was then received by Professor Huda Zoghbi and her team. The meeting provided an opportunity to discuss the progress of the projects in more detail and to identify actions requiring our help and contribution.

Prof. Huda Zoghbi, Dr. Davut Pehlivan and Dr. Bernhard Suter then summarised the key points of the conference for us:

• Ionis Pharmaceuticals intends to launch an observational study to learn more about the natural history of the disease in 2023. The Natural History Study (NHS) is expected to be conducted in the US and will be limited in size to approximately 40 people with MECP2 gene duplication. It is anticipated that the natural history study will include quarterly visits in the first year, followed by semi-annual visits in the second year of the study. Ionis Pharmaceuticals intends to interact with the FDA in 2023. However, it is important to note that this is a separate process from the submission or approval of an Investigational New Drug application (IND).

• Dr Davut Pehlivan and Dr Sameer Bajikar spoke about the genomic studies. The genomic studies continue to reveal that different types of duplication (i.e. single - complex - triple) and measured levels of MeCP2 protein will guide the dose of ASO (antisense oligonucleotides) to be administered. Recruitment for the genetic studies is underway and you can participate from all over the world.

• Dr Mirjana Maletic-Savatic spoke about biomarker studies. Biomarker discovery studies are underway. Several biomarkers have been identified that make it possible to differentiate between duplication syndrome, Rett syndrome and healthy individuals. The aim is now to expand the list of biomarkers through the NHS disease progression study and to identify one or two strong biomarkers that may reflect disease severity and response to ASO treatment.

• Dr Sarika Peters and Dr Jeff Neul spoke about progress on outcome measures. There will be an effort to develop a multi-centre clinical impression scale with the aim of using this scale in the upcoming clinical trial.

• Dr Zhenya Ivakine presented a new mouse model that expresses both MECP2 and IRAK1, with the aim of creating a better animal model for studies on the syndrome. He also gave an update on CRISPR/Cas9-based genome editing in MECP2 gene duplication. Although the results are encouraging, further laboratory studies are needed before moving on to human studies.

• Dr Ashley Anderson presented the preliminary results of a screen for MeCP2 regulators. Inhibition of these regulators could lead to new treatments, but these studies are at an early stage and need to be developed further before moving on to human studies.

• The clinical experts also spoke about common problems (e.g. gastrointestinal, epilepsy, frequent infections) in carriers of the duplication. Given that epilepsy is the main problem causing patient regression, and that there are no clear guidelines on seizure medication, they plan to launch a wide-ranging investigation.