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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacija CTNNB1 Ustanova Za Raziskave Na Podrocju Genske Terapije

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10], Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

21 Nov 2025 → ongoing

Decision date (initial)

2025-11-03

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To assess the safety and tolerability of URBAGEN administered by bilateral intracerebroventricular injection in pediatric patients with a diagnosis of CTNNB1 syndrome.

Secondary objectives 1

1. To assess the preliminary efficacy of URBAGEN as a single ICV administration in pediatric patients with CTNNB1 syndrome.

Conditions and MedDRA coding

CTNNB1 syndrome

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Male or female participant aged 2-12 years at the time of informed consent; Part A: 6-12 years; Part B: 2-12 years
2. 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
3. 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.
4. Informed consent from the parents/legal guardians of the participant.
5. Parents/legal guardians are willing and able to comply with all protocol visits and procedures.
6. 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.
7. Participant’s use of concomitant medications must be stable for at least 28 days prior to IMP dosing.
8. Parents/legal guardians must agree for the participant not to participate in any other interventional study whilst enrolled in this clinical trial.
9. 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.
10. 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.
11. 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.

Exclusion criteria 32

1. 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.
2. Participant diagnosed with a concomitant neurodevelopmental disorder unrelated to CTNNB1.
3. Participant with congenital malformation(s) significantly affecting the nervous system.
4. Participant with a history of traumatic, metabolic, vascular or infective brain injury with persistent neurological deficits per investigator’s judgement.
5. Participant has contraindications for MRI brain.
6. 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.
7. 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.
8. 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.
9. Participant has a significant congenital cardiac defect that according to the investigator represents a significant safety risk.
10. Participant has a left ventricular ejection fraction (LVEF) < or equal 50% on echocardiogram on previous assessment or at screening.
11. 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).
12. 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.
13. Participant is assessed as being unable to tolerate anesthesia required for ICV administration and/or sedation required for other study procedures.
14. Participant requiring invasive ventilatory support (e.g. endotracheal ventilation or tracheostomy) within the 6 months prior to enrolment.
15. 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)
16. Clinically significant structural abnormality on liver ultrasound (i.e. fatty liver transformation, liver cirrhosis, liver cancer)
17. 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)
18. Clinically significant structural abnormality on kidney ultrasound (i.e. absence of one kidney, horse-shoe kidney, severe abnormality of renal pelvis or urinary tract)
19. 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)
20. Participant has a history of a biopsy-confirmed malignancy.
21. Participant has a history of major surgery within six months prior to enrolment or planned surgery during first 12 months of study.
22. 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.
23. Participant tests positive for AAV9 antibody with titers >1:50 for AAV9 antibodies utilizing an enzyme linked immunospot.
24. Participant has been enrolled in another interventional clinical trial within 1 year prior to enrolment.
25. Participant has previously received gene or cell therapy.
26. 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.
27. 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.
28. Participant has a significant concurrent illness or infection within 30 days prior to dosing which could compromise safety.
29. Participant screens positive for acute Coronavirus disease 2019 (COVID-19), confirmed with PCR from a pharyngeal swab sample.
30. Participant has serologic evidence of current human immunodeficiency virus (HIV)-1 or HIV-2 infection.
31. 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)
32. 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)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 7

1. Incidence, severity, and causality of adverse events and serious adverse events.
2. Occurrence of clinically significant abnormalities in blood (blood count, renal function, liver function, coagulation), urine or CSF compared to baseline.
3. Occurrence of clinically significant changes in cardiorespiratory parameters from baseline.
4. Occurrence of new clinically significant cardiovascular abnormalities on 12-lead electrocardiogram (ECG) or echocardiogram.
5. Occurrence of clinically significant electroencephalographic changes from baseline (EEG).
6. Occurrence of clinically significant changes in head circumference and significant volumetric changes on MRI brain.
7. Presence of antibodies for AAV9 in serum.

Secondary endpoints 1

1. To assess the preliminary efficacy of URBAGEN as a single ICV administration in pediatric patients with CTNNB1 syndrome.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacija CTNNB1 Ustanova Za Raziskave Na Podrocju Genske Terapije

Sponsor organisation

Fundacija CTNNB1 Ustanova Za Raziskave Na Podrocju Genske Terapije

Address

Dalmatinova Ulica 5

City

Ljubljana

Postcode

1000

Country

Slovenia

Scientific contact point

Organisation

Fundacija CTNNB1 Ustanova Za Raziskave Na Podrocju Genske Terapije

Contact name

Špela Miroševič

Public contact point

Organisation

Fundacija CTNNB1 Ustanova Za Raziskave Na Podrocju Genske Terapije

Contact name

Špela Miroševič

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications