ADENO-ASSOCIATED VIRAL VECTOR SEROTYPE 9 CONTAINING THE HUMAN CTNNB1 GENE for CTNNB1 syndrome

Inclusion criteria

• {"criterion_text":"- Male or female participant aged 2-12 years at the time of informed consent; Part A: 6-12 years; Part B: 2-12 years\n- 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.\n- 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.\n- 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\n- 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.\n- Informed consent from the parents/legal guardians of the participant.\n- Parents/legal guardians are willing and able to comply with all protocol visits and procedures.\n- 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.\n- Participant’s use of concomitant medications must be stable for at least 28 days prior to IMP dosing.\n- Parents/legal guardians must agree for the participant not to participate in any other interventional study whilst enrolled in this clinical trial.\n- 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."}

Exclusion criteria

• {"criterion_text":"- 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.\n- Participant has a left ventricular ejection fraction (LVEF) < or equal 50% on echocardiogram on previous assessment or at screening.\n- 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).\n- 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.\n- Participant is assessed as being unable to tolerate anesthesia required for ICV administration and/or sedation required for other study procedures.\n- Participant requiring invasive ventilatory support (e.g. endotracheal ventilation or tracheostomy) within the 6 months prior to enrolment.\n- 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)\n- Clinically significant structural abnormality on liver ultrasound (i.e. fatty liver transformation, liver cirrhosis, liver cancer)\n- 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)\n- Clinically significant structural abnormality on kidney ultrasound (i.e. absence of one kidney, horse-shoe kidney, severe abnormality of renal pelvis or urinary tract)\n- 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)\n- Participant diagnosed with a concomitant neurodevelopmental disorder unrelated to CTNNB1.\n- Participant has a history of a biopsy-confirmed malignancy.\n- Participant has a history of major surgery within six months prior to enrolment or planned surgery during first 12 months of study.\n- 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.\n- Participant tests positive for AAV9 antibody with titers >1:50 for AAV9 antibodies utilizing an enzyme linked immunospot.\n- Participant has been enrolled in another interventional clinical trial within 1 year prior to enrolment.\n- Participant has previously received gene or cell therapy.\n- 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.\n- 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.\n- Participant has a significant concurrent illness or infection within 30 days prior to dosing which could compromise safety.\n- Participant screens positive for acute Coronavirus disease 2019 (COVID-19), confirmed with PCR from a pharyngeal swab sample.\n- Participant with congenital malformation(s) significantly affecting the nervous system.\n- Participant with a history of traumatic, metabolic, vascular or infective brain injury with persistent neurological deficits per investigator’s judgement.\n- Participant has contraindications for MRI brain.\n- 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.\n- 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.\n- 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.\n- Participant has a significant congenital cardiac defect that according to the investigator represents a significant safety risk."}

Primary endpoints

• {"endpoint_text":"- Incidence, severity, and causality of adverse events and serious adverse events.\n- Occurrence of clinically significant abnormalities in blood (blood count, renal function, liver function, coagulation), urine or CSF compared to baseline.\n- Occurrence of clinically significant changes in cardiorespiratory parameters from baseline.\n- Occurrence of new clinically significant cardiovascular abnormalities on 12-lead electrocardiogram (ECG) or echocardiogram.\n- Occurrence of clinically significant electroencephalographic changes from baseline (EEG).\n- Occurrence of clinically significant changes in head circumference and significant volumetric changes on MRI brain.\n- Presence of antibodies for AAV9 in serum.","definition_or_measurement_approach":"- Measured by reporting and assessment of adverse events and serious adverse events including causality assessment.\n- Laboratory, urine and CSF tests compared to baseline values to detect clinically significant abnormalities.\n- Cardiorespiratory parameters measured and compared to baseline assessments.\n- 12-lead ECG and echocardiogram assessments to detect new clinically significant cardiovascular abnormalities.\n- EEG assessments compared to baseline to identify clinically significant changes.\n- Head circumference measurements and MRI brain volumetric analyses compared to baseline.\n- Serologic testing for antibodies to AAV9 in serum."}

Secondary endpoints

• {"endpoint_text":"- To assess the preliminary efficacy of URBAGEN as a single ICV administration in pediatric patients with CTNNB1 syndrome.","definition_or_measurement_approach":"- Assessment of preliminary efficacy of URBAGEN following single ICV administration (no further measurement details provided in the extracted record)."}

Slovenia

Earliest CTIS Part Ii Submission Date

24-10-2025

Latest Decision Or Authorization Date

27-03-2026

Processing Time Days

154

Number Of Sites

1

Number Of Participants

12

Primary sponsor

Full Name

Fundacija CTNNB1 Ustanova Za Raziskave Na Podrocju Genske Terapije

Organisation Type

Laboratory/Research/Testing facility

Country Of Registered Address

Slovenia