Rett Syndrome

MECP2 Duplication Syndrome (MDS) is a rare genetic disorder mostly affecting males, causing severe intellectual disability, motor problems, low muscle tone in infancy, epilepsy, frequent respiratory infections, and often leading to early death before age 25. This condition is caused by extra copies of the MECP2 gene, which is important for brain development and function. Researchers are studying HG204, a new CRISPR RNA-editing therapy designed to reduce the levels of MECP2 protein in the brain and improve symptoms in affected individuals. HG204 uses a special technology called high-fidelity Cas13Y delivered by a single adeno-associated virus vector. The therapy is given as a single injection directly into the brain's ventricles. The study plans to evaluate two dose groups to assess safety and effectiveness. The treatment phase includes a screening period of 8 weeks, followed by the injection visit and a 52-week follow-up to monitor effects and safety. Participants will be closely monitored during this study lasting about 60 weeks, including initial screening, treatment, and follow-up visits. Researchers will track any side effects and changes in clinical status using various developmental and behavioral assessments. Laboratory tests and imaging will be used to evaluate health status, and the primary outcome is the incidence and severity of adverse events over 52 weeks. The study aims to gather detailed information on the safety and potential benefits of HG204 for patients with MDS.

Researchers are evaluating the safety and effectiveness of an investigational gene therapy called NGN-401 in females diagnosed with typical Rett syndrome. This pivotal phase 3 study, named Embolden, is an open-label and single-arm trial conducted at multiple centers. NGN-401 uses a viral vector to deliver a full-length human MECP2 gene designed to produce therapeutic levels of MeCP2 protein while avoiding overexpression. The study treatment involves a single dose of NGN-401 delivered directly into the brain's ventricles under general anesthesia. Participants receive one administration and will be monitored for 3 years to assess the therapy's effects. After this period, they are expected to join a long-term follow-up study lasting 12 years. Different dosing levels are planned for various age groups starting from 3 years old. Participants will have regular assessments to monitor efficacy and safety throughout the study. Caregivers and participants must live within a two-hour drive of the study center for at least three months post-treatment. The main outcome measured is the efficacy of NGN-401 after 52 weeks. Researchers will also observe and document any side effects or tolerability issues during the study and long-term follow-up.

Researchers are studying TSHA-102 gene therapy in females with typical Rett syndrome, a genetic condition caused by mutations in the MECP2 gene. The study aims to evaluate the safety of a single dose of TSHA-102 given into the spinal fluid and to find the dose with the best balance of safety and potential benefit. This trial includes phases 1, 2, and 3, with initial dose-finding followed by evaluation of efficacy and safety at the selected dose. The study involves two parts: Part A, which assessed safety and dose levels with two doses of TSHA-102 in 6 participants, and Part B, which evaluates the chosen dose in 15 females aged 6 to under 22 years. TSHA-102 is a gene therapy delivered once through an injection into the spinal fluid (intrathecal administration). Participants receive only one dose during the study. Participants are followed for five years after treatment to monitor safety and outcomes. Researchers will assess safety and tolerability during the first year and evaluate efficacy outcomes over the same period. Participants will have regular visits for medical assessments, and their progress will be tracked long-term to understand the effects and safety of TSHA-102.

Researchers are evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of the drug ION440 in people with Methyl CpG Binding Protein 2 (MECP2) Duplication Syndrome (MDS). This phase 1-2 randomized, double-blind, sham-controlled study includes both pediatric and adult participants to better understand how ION440 affects this rare genetic condition. The study is sponsored by Ionis Pharmaceuticals, Inc. and aims to carefully monitor treatment impacts over time. Participants will be randomly assigned to receive one of three different doses of ION440 or a sham procedure during the first part of the study, which lasts about 36 weeks. ION440 is given by injection into the spinal fluid (intrathecal bolus). After completing the first part, participants may enter a second open-label extension lasting up to approximately 156 weeks, where they receive the same dose of ION440 as before. The study includes two age groups: children aged 2 to 7 years and participants aged 8 to 65 years. The dosing groups are evaluated sequentially, starting with the older group. During the study, participants will undergo physical and neurological exams, vital sign checks, lab tests, electrocardiograms, and monitoring for any adverse effects. Blood and cerebrospinal fluid samples will be collected to measure drug levels. The study will assess the number of participants experiencing treatment-related side effects and changes in health markers over both the initial 36-week period and the longer extension. Participants are expected to complete all study visits and procedures to support these evaluations, which together may last more than three years.

This research studies how the brain processes sound in people with Rett syndrome, a genetic neurodevelopmental condition. It aims to better understand brain activity and clinical features related to Rett syndrome by observing brain responses to simple sounds and collecting detailed health and behavior information. The study is observational and includes both individuals with Rett syndrome and healthy controls matched by age and sex. Participants with Rett syndrome will undergo a noninvasive electroencephalogram (EEG) while listening to simple sounds through headphones. Parents or caregivers will fill out questionnaires and may participate in interviews about symptoms, communication skills, and daily functioning. Clinicians may also assess Rett syndrome severity. Control participants will have EEG recordings and complete a demographics questionnaire. No treatments or medications are given in this study. Participants will attend a single study visit lasting up to one day, during which EEG recordings and assessments take place. Researchers will measure brain response amplitude and timing to sounds, along with clinical scores such as Rett syndrome severity and communication ability. Safety and comfort during EEG are monitored. The total time commitment is limited to this one visit, supporting minimal disruption for participants.

The Brain Imaging in Babies Study (BIBS) aims to better understand how a baby's brain develops from before birth up to 3 to 4 years old. It includes children from diverse backgrounds and uses advanced tools like MRI scans along with behavioral assessments to gather early information on infant brain development. The study also seeks to identify early brain features that might help predict if a child will develop traits of conditions such as Autism Spectrum Disorder (ASD) or Attention Deficit Hyperactivity Disorder (ADHD). Since 2020, the study has included testing for COVID-19 in mothers and babies to explore how infections affect development. This observational study involves pregnant mothers with and without confirmed COVID-19 and their infants, including those with and without a family history of ASD or neurodevelopmental conditions. The study uses safe MRI scanning, which produces detailed brain images without X-rays. Participants are based in England, UK, and the study welcomes a broad range of participants to capture diverse developmental data. Participants will undergo MRI scans and behavioral assessments to evaluate brain development and neurodevelopmental outcomes by 3 to 4 years of age. The research team monitors children's development over time, including COVID-19-related factors in mothers and babies. The study continues to collect data until 2028 to provide long-term insights into early brain growth and developmental conditions.

Researchers are exploring cognitive functions in individuals with Rett Syndrome (RTT), a severe intellectual and developmental disability, using eye-tracking tasks. These tasks help assess attention and learning while minimizing the impact of motor and verbal difficulties common in RTT. The study aims to understand if these measures change over time or with health status changes, especially during treatment with the recently FDA-approved drug trofinetide. This observational study follows a within-subject design involving participants initiating trofinetide treatment. It includes two pre-treatment assessments and one post-treatment assessment at 4 weeks, with optional follow-up visits up to 12 months later. The non-invasive measures include eye-tracking tasks, heart rate variability, and autonomic function evaluations to monitor changes in attention, oculomotor control, learning, and heart function. Participants will undergo assessments at baseline, after 6 weeks, and up to 12 months, including measurements of eye movement gaze fixations, heart rate variability, and heart rate suppression. Families interested in further follow-up can take part in additional visits aligned with standard care or research-only appointments. The study monitors cognitive and physiological responses during trofinetide treatment to better understand its impact over time.

Researchers are evaluating a new treatment approach for patients with large brain tumors or brain metastases using a combination of two types of precise radiation therapy machines: the linear accelerator and the Gamma Knife. This study aims to see if combining these technologies can improve tumor control and reduce side effects compared to the current standard treatment, which uses only the linear accelerator. The researchers believe that the break between treatments and the unique qualities of each machine may help protect healthy brain tissue better and control the tumor more effectively. The treatment plan involves first giving patients four daily radiation treatments with the linear accelerator. After these treatments, there is a 1-2 week break during which new scans are taken to assess tumor shrinkage and better target any remaining tumor areas. The final treatment is then delivered using the Gamma Knife, which provides very precise radiation to the tumor while sparing healthy tissue. This combined approach is being studied in a prospective, single-arm Phase II trial. Participants will be monitored closely throughout the study and for up to 24 months after treatment. Researchers will assess the safety and effectiveness of the combined therapy by measuring late local complications, tumor control, survival, brain progression, radiation side effects, neurological function, and quality of life. Regular imaging scans and clinical evaluations will be done to track outcomes and side effects. The total study duration includes treatment and long-term follow-up to understand the benefits and risks of this new treatment strategy.

This research aims to validate the use of CRISPR/Cas9 gene editing combined with AAV-based delivery to correct the most common MECP2 gene mutations associated with Rett syndrome. The project focuses on both laboratory cell models and live animal models to better understand this personalized gene therapy approach. The principal investigator's lab is part of a European network specializing in rare intellectual and neurodevelopmental disorders. The study involves testing gene editing efficiency in human cell cultures derived from female patients diagnosed with Rett syndrome who have specific recurrent MECP2 mutations. The gene editing is conducted in vitro using these cellular models to observe correction potential. This approach is observed over a period to assess both editing efficiency and specificity. Participants are female patients aged over 6 months with genetically confirmed Rett syndrome involving particular MECP2 mutations. Parents or legal guardians provide informed consent for participation. Researchers monitor gene editing outcomes such as efficiency and specificity over a three-year timeframe. The study does not involve treatment administration but focuses on laboratory validation of gene editing techniques.

Researchers are studying adults with rare and complex genetic syndromes that affect multiple body systems and often include intellectual disability. These patients typically receive specialized care from multiple specialists during childhood, but as medical advances have extended life expectancy, many are now living into adulthood. The study aims to understand the medical needs, comorbidities, medication use, and quality of life impacts for adults with these rare syndromes, addressing a gap in adult care and guidelines. This research involves a retrospective review of medical files, including medical history, laboratory results, additional tests, and records of physical and psychological complaints. There is no active treatment or intervention, as the study collects and analyzes existing data to gain insights about health issues and medication adaptations needed for these syndromes. Participants' medical records will be analyzed to evaluate the presence of physical health problems, laboratory values, physical and psychological complaints, and medication use over a one-year period. The study uses statistical software for analysis and aims to improve understanding of adult care needs for these rare genetic conditions. The study began in October 2018 and will continue through January 2030.