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GAIN-CTNNB1: A Phase I/II open-label trial to evaluate the safety, tolerability, and preliminary efficacy of a single intracerebroventricular administration of an AAV9-based gene replacement therapy in paediatric patients with CTNNB1 syndrome
EU CTIS ID: 2025-522719-40-00
What this study is testing
To assess the safety and tolerability of URBAGEN administered by bilateral intracerebroventricular injection in pediatric patients with a diagnosis of CTNNB1 syndrome.
- Phase I and Phase II (Integrated)- First administration to humans
A plain-language read of the study's public EU CTIS listing. The study team confirms the details.
Who can take part
You may be able to join if
- Male or female participant aged 2-12 years at the time of informed consent; Part A: 6-12 years; Part B: 2-12 years
- Female participants who are post-menarcheal must have a negative urine pregnancy test at screening and and be willing to have additional pregnancy tests during the study.
- Participant’s parents/legal guardians must agree to refrain from future donation of the participant’s blood, blood products, tissue, and organs after receiving the IMP due to theoretical risks associated with AAV genome persistence in tissues.
- Child aged 4 to 12 years has to weigh at least 13,3 kg: 5,0E+14 vg; Child aged 3 years has to weigh at least 11,96 kg: 4,5E+14 vg; Child aged 2 years has to weigh at least 10,94 kg: 4,11E+14 vg
- Genetically confirmed diagnosis of CTNNB1 syndrome with a heterozygous pathogenic or likely pathogenic variant in the CTNNB1 gene (Class 4/5 according to American College of Medical Genetics and Genomics), confirmed by geneticist at screening.
- Informed consent from the parents/legal guardians of the participant.
You likely can't join if
- Participant has a mutation in the CTNNB1 gene which is predicted to result in a gain-of-function effect (e.g. p.G575R) or dominant-negative effect (e.g. p.Y333*, p.Q193*, p.A317Vfs8* and p.S352fs*) on the Wnt/β-catenin pathway, or any variant that, in the opinion of the PI, is inconsistent with the mechanism of action of the gene replacement therapy.
- Participant has a left ventricular ejection fraction (LVEF) < or equal 50% on echocardiogram on previous assessment or at screening.
- Participants with clinically significant cardiovascular abnormalities, including clinically significantly prolonged QT interval in ECG (QT interval corrected using Fridericia's formula (QTcF) ≥450 ms at screening).
- Participant has a concomitant genetic diagnosis or neurodevelopmental syndrome that in the opinion of the investigator could interfere with safety, ability to perform assessments, or data interpretation.
- Participant is assessed as being unable to tolerate anesthesia required for ICV administration and/or sedation required for other study procedures.
- Participant requiring invasive ventilatory support (e.g. endotracheal ventilation or tracheostomy) within the 6 months prior to enrolment.
See the full eligibility criteria
Who can join
- Male or female participant aged 2-12 years at the time of informed consent; Part A: 6-12 years; Part B: 2-12 years
- Female participants who are post-menarcheal must have a negative urine pregnancy test at screening and and be willing to have additional pregnancy tests during the study.
- Participant’s parents/legal guardians must agree to refrain from future donation of the participant’s blood, blood products, tissue, and organs after receiving the IMP due to theoretical risks associated with AAV genome persistence in tissues.
- Child aged 4 to 12 years has to weigh at least 13,3 kg: 5,0E+14 vg; Child aged 3 years has to weigh at least 11,96 kg: 4,5E+14 vg; Child aged 2 years has to weigh at least 10,94 kg: 4,11E+14 vg
- Genetically confirmed diagnosis of CTNNB1 syndrome with a heterozygous pathogenic or likely pathogenic variant in the CTNNB1 gene (Class 4/5 according to American College of Medical Genetics and Genomics), confirmed by geneticist at screening.
- Informed consent from the parents/legal guardians of the participant.
- Parents/legal guardians are willing and able to comply with all protocol visits and procedures.
- Parents/legal guardians are willing and able to reside within 1 hour of the site at which the clinical trial will be conducted for at least 4 months post-dosing. Parents/legal guardians will be informed that this period may be increased in the case of a safety event or concern.
- Participant’s use of concomitant medications must be stable for at least 28 days prior to IMP dosing.
- Parents/legal guardians must agree for the participant not to participate in any other interventional study whilst enrolled in this clinical trial.
- Investigator will check vaccination status of each participant and evaluate and confirm its appropriateness per age and participant’s home country. The last vaccination dose must be received a minimum of 30 days prior to the start of immunosuppressants.
What rules you out
- Participant has a mutation in the CTNNB1 gene which is predicted to result in a gain-of-function effect (e.g. p.G575R) or dominant-negative effect (e.g. p.Y333*, p.Q193*, p.A317Vfs8* and p.S352fs*) on the Wnt/β-catenin pathway, or any variant that, in the opinion of the PI, is inconsistent with the mechanism of action of the gene replacement therapy.
- Participant has a left ventricular ejection fraction (LVEF) < or equal 50% on echocardiogram on previous assessment or at screening.
- Participants with clinically significant cardiovascular abnormalities, including clinically significantly prolonged QT interval in ECG (QT interval corrected using Fridericia's formula (QTcF) ≥450 ms at screening).
- Participant has a concomitant genetic diagnosis or neurodevelopmental syndrome that in the opinion of the investigator could interfere with safety, ability to perform assessments, or data interpretation.
- Participant is assessed as being unable to tolerate anesthesia required for ICV administration and/or sedation required for other study procedures.
- Participant requiring invasive ventilatory support (e.g. endotracheal ventilation or tracheostomy) within the 6 months prior to enrolment.
- Participant has clinically significant liver disease, defined as any of: Aspartate aminotransferase >3,0 x ULN (Grade 1 CTCAE v5.0); Alanine aminotransferase >3,0 x ULN (Grade 1 CTCAE v5.0); Gamma-glutamyl transferase >2,5 x ULN (Grade 1 CTCAE v5.0); Bilirubin >1,5 x ULN (Grade 1 CTCAE v5.0)
- Clinically significant structural abnormality on liver ultrasound (i.e. fatty liver transformation, liver cirrhosis, liver cancer)
- Participant has clinically significant renal disease or impairment that could affect safety: Creatinine (>1,5 ULN) (Grade 1 CTCAE v5.0); GFR <50% LLN (Grade 1 CTCAE v5.0)
- Clinically significant structural abnormality on kidney ultrasound (i.e. absence of one kidney, horse-shoe kidney, severe abnormality of renal pelvis or urinary tract)
- Participant has any of the following abnormal, clinically significant laboratory test results during screening. A single repeat will be permitted: Significant thrombocytopenia (Platelet count <150E9/L); Neutropenia (Absolute neutrophil count <1E9/L); Persistent leukopenia: <2E9/L or leukocytosis: >20E9/L; Significant anemia (hemoglobin <100 g/L); Abnormal coagulation (prothrombin time or partial thromboplastin time above ULN)
- Participant diagnosed with a concomitant neurodevelopmental disorder unrelated to CTNNB1.
- Participant has a history of a biopsy-confirmed malignancy.
- Participant has a history of major surgery within six months prior to enrolment or planned surgery during first 12 months of study.
- Participant has any other significant concomitant medical disorder which could confound the interpretation of safety or efficacy data as determined by PI or medical monitor.
- Participant tests positive for AAV9 antibody with titers >1:50 for AAV9 antibodies utilizing an enzyme linked immunospot.
- Participant has been enrolled in another interventional clinical trial within 1 year prior to enrolment.
- Participant has previously received gene or cell therapy.
- Participant has a known allergy or hypersensitivity to any ingredients or excipients of the IMP, or to immunosuppressants or pre-medications specified within the trial protocol.
- Participant with a history of receiving immune-modulating agents (such as chemotherapy, radiotherapy, intravenous steroids, other immunosuppressive agents) within 3 months prior to dosing. Topical or inhaled corticosteroid treatment may be permitted at the discretion of the investigator.
- Participant has a significant concurrent illness or infection within 30 days prior to dosing which could compromise safety.
- Participant screens positive for acute Coronavirus disease 2019 (COVID-19), confirmed with PCR from a pharyngeal swab sample.
- Participant with congenital malformation(s) significantly affecting the nervous system.
- Participant has serologic evidence of current human immunodeficiency virus (HIV)-1 or HIV-2 infection.
- Participant has acute or chronic hepatitis B or C infections, including: Serologic evidence of hepatitis C infection (positive core antibody) and Serologic evidence of acute or chronic active hepatitis B (positive core antibody and/or positive surface antigen)
- Participant is assessed as being unable to undergo surgical procedure or has a preexisting condition that could be worsened by the surgical procedure (i.e. preexisting hydrocephalus)
- Participant with a history of traumatic, metabolic, vascular or infective brain injury with persistent neurological deficits per investigator’s judgement.
- Participant has contraindications for MRI brain.
- Participant has a clinically significant increase in seizure frequency as determined by the investigator or clinically documented episode of generalized status epilepticus (≥30-minute generalized tonic-clonic seizure) within 4 weeks of the baseline visit.
- Participant has severe contractures, as determined by the investigator at screening, which are considered likely to interfere with their ability to complete assessments of motor function.
- Participant has increased intracranial pressure, tumor, vascular abnormality, or any major structural anomaly which could complicate or increase the risk of ICV administration of the IMP. Or the participant has any other contraindication to the ICV procedure.
- Participant has a significant congenital cardiac defect that according to the investigator represents a significant safety risk.
The study team makes the final eligibility decision.
Questions & answers
Do participants get paid in this trial?
This listing doesn't specify compensation. Many trials still reimburse travel or offer a stipend, so it's worth asking the study team when you connect.
Is it free to join, and do I need insurance?
Searching and applying through BridgeMD is free. In clinical trials the study-related treatment and visits are generally provided at no cost to you. You usually don't need insurance to take part - confirm specifics with the study team.
How long does this study last?
The listing doesn't state an exact length. The study team walks you through the schedule and number of visits before you decide to enroll.
Who can join this trial?
This study is enrolling all sexes, 0-17 years. The study team makes the final eligibility decision.
Explore other conditions
BridgeMD is an information and trial-matching tool - not medical advice, and not the study sponsor. Details come from EU CTIS; the study team decides eligibility.