The GAIN-CTNNB1 Phase I/II clinical trial includes children aged 2-12 years with a genetically confirmed diagnosis of CTNNB1 syndrome. However, for safety reasons, the trial begins with an older age group:
Part A (first cohort), 6-12 years: This group is treated first because their age most closely matches the developmental stage used in preclinical animal studies and provides the safest starting point for a first-in-human trial.
Part B (subsequent cohorts), 2-12 years: Once safety is confirmed in the first cohort, the same trial will expand to include younger children aged 2-5 years.

Will older children or adolescents be included later? If safety and early efficacy are demonstrated, the trial may later open to older children and adolescents (up to 18 years).

What about adults? Adults are not part of this first study because safety and dosing must first be established in children, and younger brains are expected to benefit most. In the future, if the therapy proves safe and effective, it may be possible to expand to older teenagers and adults.

The clinical trial will take place at the University Medical Centre Ljubljana (Ljubljana, Slovenia).

The Principal Investigator of the clinical trial is Dr. Damjan Osredkar, Head of the Pediatric Neurology Department at University Medical Centre Ljubljana, supported by a specialist team including neurosurgeons, clinicians, nurses, psychologists, physiotherapists and more.

We are exploring possibilities for additional international sites, but at this time, clinical trial is available only in Slovenia.

After you email gain@ctnnb1-foundation.org, the medical team will contact you and send a short questionnaire. This helps the clinical and ethics teams assess whether your child may be a suitable candidate for the trial. If the initial information suggests a good fit, the medical team will then invite your family for an interview to discuss the trial in more detail and review the next steps.

Before your child can receive the study drug, he/she will have to be assessed if he/she is a suitable candidate to receive the study drug and participate in the study. Even if the child is compatible with the eligibility criteria, it is possible he/she might not be enrolled in the study. Possible reasons include investigator’s or sponsor’s decision, or if the study has been halted, the study has enrolled the maximum number of participants, or study drug is not available.

If the medical and ethics teams determine that your child may be a good candidate, your family will be invited to Ljubljana for screening. Please note that your child is not officially enrolled until screening is completed and eligibility is confirmed. Below are the steps that follow:

a) Screening period (up to several weeks): Screening takes place before any treatment can begin. During this period, your child will undergo the necessary medical tests to confirm eligibility, such as MRI, blood and urine tests, neurological and physical examinations, heart and abdominal ultrasounds, anaesthesia evaluation, viral and immune testing. Screening ensures it is safe to proceed.

b) Baseline period (3 days): Once screening is completed, your child will enter a short baseline phase. During these days, the medical team will: start immunosuppression, perform baseline neurological and developmental evaluations, collect blood and urine samples, confirm that all preparations for treatment are complete. This establishes the “before treatment” reference point.

c) Hospital admission (1 day before treatment): Your child will be admitted to the hospital the day before gene therapy administration for final checks, including physical and neurological exams, safety laboratory tests, and anaesthesia confirmation

d) Gene therapy procedure (Day 0): Your child will receive URBAGEN through a short ICV neurosurgical procedure. A small sample of CSF will also be collected for safety testing.

e) Early post-treatment monitoring (about 1 week in hospital): After treatment, your child will remain in the hospital for several days for daily medical exams, blood and urine tests, neurological checks, monitoring for any early reactions or side effects.

f) Stay near the hospital (about 4 months): After discharge, your family will need to stay close to University Medical Centre Ljubljana for regular follow-up visits and close monitoring of your child’s progress.

g) Long-term follow-up (5 years): Following the first months, your child will be followed for a total of five years with a mix of in-person and remote visits. This long-term follow-up is required for all gene therapy trials to ensure continued safety and to track developmental progress.

Because this is a first-in-human clinical trial, there may be risks that are currently unknown. These risks may arise from the study drug (URBAGEN), from the medical procedures involved, or from other aspects of this study which may include situations that could make your child sick, feel uncomfortable or harm your child.

Your child’s condition may get better, but it could stay the same or even get worse, in worst case it can lead to death. In case of side effects, the study team may give your child medicines to help reduce side effects. These side effects may be mild or severe. There is no guarantee that the study drug will have a positive therapeutic effect on improving your child’s CTNNB1 syndrome. This means that your child may continue to experience worsening developmental delays, motor challenges, and other characteristics of CTNNB1 syndrome over time.

In rare cases, the study drug could cause serious long-term consequences. These could include damage to the liver, immune system complications, or even the development of certain types of cancer. If such side effects occur, your child might need long-term medical treatment, frequent hospital visits, or even life-long monitoring and care.

There is no guarantee that your child will personally benefit from taking part in this study. Information from this study will help investigators and the Sponsor learn more about URBAGEN as a treatment for CTNNB1 syndrome. Results from this study may benefit others in the future. Your child may feel that they are benefiting in the following ways:

• Close medical monitoring: your child’s health and condition will be closely monitored throughout the study. This includes regular medical assessments and tests, which may help identify health issues early. Please note that the study-related evaluations and procedures are not intended to replace your child’s regular medical care. You should continue follow-up with your child’s personal physician as usual.
• Possible symptom improvement: The study drug may improve some symptoms of CTNNB1 syndrome, but this cannot be predicted and may vary from one participant to another.

In preclinical studies on mice, treatment led to noticeable improvements in certain behavioral tests, with increased activity, exploratory behavior, and greater spontaneous activity (which may also be associated with lower anxiety) observed, movement improved, as confirmed by detailed analyses of gait and joint position, and changes were observed that indicate improved motor function. In addition, analyses showed increased expression of the added CTNNB1 gene and increased levels of beta-catenin protein in key areas of the brain, confirming that the gene is indeed expressed in the brain after treatment. These data suggest that treatment can correct certain functional characteristics in mice, but this does not necessarily mean that the treatment will be equally effective in children.

The gene therapy itself is provided free of charge to all participants in the clinical trial.

However, families will need to cover the costs of travel to Slovenia and accommodation during the required four-month stay near the hospital, as well as any travel expenses related to follow-up visits.

The CTNNB1 Foundation will support selected families with fundraising efforts to help cover these costs and associated hospital-related expenses.