Urbagen gene replacement for children with CTNNB1 neurodevelopmental syndrome

GAIN-CTNNB1: A Phase I/II Open-Label Trial To Evaluate the Safety, Tolerability, and Preliminary Efficacy of Intracerebroventricular Administration of an AAV9 Based Gene Replacement Therapy in Paediatric Patients With CTNNB1 Neurodevelopmental Syndrome

This trial will try a one-time AAV9 gene replacement called Urbag en, delivered into the brain, to see if it is safe and helps children aged 2–12 with CTNNB1 neurodevelopmental syndrome.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 12 (estimated)
• Ages: 2 Years to 12 Years
• Sex: All
• Sponsor: CTNNB1 Foundation (Academic / other)
• Drugs / interventions: chemotherapy
• Locations: 1 site (Ljubljana)
• Trial ID: NCT07270549 on ClinicalTrials.gov

What this trial studies

This first-in-human Phase 1/2 trial gives a single bilateral intracerebroventricular (ICV) infusion of an AAV9 vector carrying the CTNNB1 gene (Urbagen) to pediatric patients with genetically confirmed CTNNB1 syndrome. Participants receive prophylactic immunosuppression (methylprednisolone and sirolimus) and are monitored closely for safety and immune responses. Clinical outcomes include motor, cognitive, behavioral, sleep, and quality-of-life measures with scheduled follow-up visits over three years. The protocol uses weight-based dosing and requires genetic confirmation and local residence near the dosing site for early monitoring.

Who should consider this trial

Good fit: Children aged 2–12 with a genetically confirmed heterozygous pathogenic CTNNB1 variant who meet the weight-based dosing thresholds, have parental consent, and can stay near the study site for required monitoring are ideal candidates.

Not a fit: Patients without a confirmed pathogenic CTNNB1 variant, those who are medically ineligible for neurosurgical ICV infusion or immunosuppression, or those with advanced irreversible neurological damage may be unlikely to benefit.

Why it matters

Potential benefit: If successful, Urbag en could restore CTNNB1 function in the brain and improve motor, cognitive, behavioral, sleep, and overall quality-of-life outcomes for affected children.

How similar studies have performed: AAV9-based CNS gene therapies have produced clinical benefit in conditions such as spinal muscular atrophy, but gene replacement for CTNNB1 is novel and this is the first-in-human trial for this condition.

Eligibility criteria

Inclusion Criteria:

* Male or female participant aged 2-12 years at the time of informed consent (Part A: 6-12 years, Part B: 2-12 years).
* 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.
* 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.
* 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.
* Participant's use of concomitant medications must be stable for at least 28 days prior to IMP dosing.

Exclusion Criteria:

* 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 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 tests positive for AAV9 antibody with titers \>1:50 for AAV9 antibodies utilizing an enzyme linked immunospot.
* 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 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)
  * Serologic evidence of acute or chronic active hepatitis B (positive core antibody and/or positive surface antigen)
* Participant diagnosed with a concomitant neurodevelopmental disorder unrelated to CTNNB1.
* Participant with congenital malformation(s) significantly affecting the nervous system.
* 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.
* Participant has a left ventricular ejection fraction (LVEF) \< 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 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.
* 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.
* Participant has any of the following abnormal, clinically significant laboratory test results during screening. A single repeat will be permitted.

  * Significant thrombocytopenia (Platelet count \<150 x 109/L)
  * Neutropenia (Absolute neutrophil count \<1 x 109/L)
  * Persistent leukopenia: \<2 x 109/L or leukocytosis: \>20 x 109/L
  * Significant anemia (hemoglobin \<100 g/L)
  * Abnormal coagulation (prothrombin time or partial thromboplastin time above ULN)
* 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 has been enrolled in another interventional clinical trial within 1 year prior to enrolment.
* Participant has previously received gene or cell therapy.

Where this trial is running

Ljubljana

• University Medical Centre Ljubljana — Ljubljana, Slovenia (Recruiting)

Study contacts

• Study coordinator: Damjan Osredkar, MD, PhD

Conditions CTNNB1 Neurodevelopmental Syndrome; CTNNB1 neurodevelopmental syndrome; AAV9 mediated gene replacement therapy; Gene replacement therapy; Gene addition therapy; Gene therapy; Clinical trial