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NCT Number: NCT07270549

Gene Replacement Therapy for Treatment of Paediatric Patients With CTNNB1 Neurodevelopmental Syndrome

The goal of this first in human, phase I/II clinical trial is to evaulate the safety, tolerability, and preliminary efficacy of AAV9 mediated gene replacement therapy (Urbagen) in paediatric patients with CTNNB1 neurodevelopmental disorder. The main questions it aims to answer are:

* Is the gene therapy with Urbagen safe and well tolerated? * Does the gene therapy improve motor function, cognitive function, behavior, sleep, and/or quality of life?

Participants will:

* Undergo screening assessments to ensure eligibility. * Recieve a single dose of gene therapy via bilateral intracerebroventricular administration. * Recieve prophylactic immunosuppresants (methylprednisolone, sirolimus). * Attend follow-up visits for safety monitoring and clinical assessments over the course of three years.

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Key information

Conditions

CTNNB1 Neurodevelopmental Syndrome

Age range

2 year–12 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

University Medical Centre Ljubljana

Ljubljana, 1000, Slovenia

Location status: Recruiting

Location contact

Damjan Osredkar, MD, PhD

CONTACT

[email protected]

0038615229273

Damjan Osredkar, MD, PhD

PRINCIPAL_INVESTIGATOR

David Gosar, PhD

SUB_INVESTIGATOR

Nina Žakelj, MD

SUB_INVESTIGATOR

Peter Spazzapan, PhD

SUB_INVESTIGATOR

About this study

CTNNB1 syndrome is a severe monogenic neurodevelopmental disorder caused by de novo mutations in the CTNNB1 gene. It presents with global developmental delay, spastic dystonic motor impairment, intellectual disability, absent or minimal speech, and a high prevalence of autistic traits.

Urbagen is an investigational gene addition therapy designed to restore functional CTNNB1 expression and improve neurological and developmental outcomes in affected patients. It is a recombinant, single-stranded adeno-associated viral vector serotype 9 (AAV9) encoding the human CTNNB1 gene under the control of the cytomegalovirus enhancer/chicken-β actin hybrid (CBh) promoter. The AAV9 vector facilitates targeted delivery to the central nervous system (CNS), crossing the blood-brain barrier (BBB) and ensuring localized gene expression to address the neurological deficits associated with CTNNB1 syndrome. The therapy is designed as a single-dose bilateral intracerebroventricular (ICV) infusion. The ICV route was selected based on its ability to achieve widespread CNS transduction while minimizing peripheral exposure, as demonstrated in preclinical models.

The goal of this first in human, phase I/II clinical trial to establish the safety, tolerability, and preliminary efficacy of AAV9 mediated gene replacement therapy (Urbagen) in paediatric patients with CTNNB1 syndrome. Urbagen has received orphan drug designation by European Medicines Agency (EMA). The clinical trial was approved by EMA/JAZMP.

This is a monocentric trial conducted at the University Children's Hospital, University Medical Centre Ljubljana, Slovenia. Twelve international participants will receive a single dose of Urbagen via bilateral intracerebroventricular administration. Prophylactic immunosuppresants (methylprednisolone, sirolimus) will be used to reduce the risks of immune-mediated complicationts. Participants will be assessed with a variety of tests during the screening and follow-up period with a total follow up of 5 years.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Urbagen gene addition therapy

Biological

Urbagen is a non-replicating single-stranded adeno-associated viral vector 9 encoding for the human β-catenin protein (AAV9/hCTNNB1 vector). It is administered as a single bilateral ICV infusion.

sirolimus

Drug

The use of sirolimus will be consistent with other AAV-9 gene therapy protocols. On Day -7 prior to the administration of URBAGEN, participants will receive a loading dose of sirolimus (3 doses of 1 mg/m2 every four hours). The following day, participants will begin a maintenance dose of sirolimus (0,5 mg/m2/day in 2 divided doses daily), which they will continue for a minimum of 10 months.

Methylprednisolone (Corticosteroid)

Drug

The use of methylprednisolone will be consistent with other AAV-9 gene therapy protocols. On the day of dosing (Day 0), participants will receive a dose of IV methylprednisolone (10 mg/kg to a maximum single dose of 500 mg, infused over 30 minutes). On Day -1 prior to administration of URBAGEN, participants will begin a course of oral prednisolone (1,0 mg/kg/day, maximum dose 30 mg daily). Prednisolone administration will continue for a minimum of four months, followed by a gradual tapering schedule.

Primary outcomes

  1. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

    Time frame: 5 years (multiple timepoints)

    Monitoring for treatment-emergent adverse events and serious adverse events in all participants.

Secondary outcomes

  1. Improvement in motor function as measured by the Bayley Scale of Infant Development 4.

    Time frame: 5 years (multiple timepoints)

    The Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4), is a standardized assessment used to evaluate developmental functioning in infants and young children across cognitive, language, and motor domains. Composite scores are standardized with a mean of 100 and a standard deviation of 15, typically ranging from 40 to 160. Higher scores indicate better developmental performance, while lower scores reflect increasing levels of developmental delay.

  2. Improvement in motor function as measured by the Wearable Syde Device (in ambulant patients).

    Time frame: 5 years (multiple timepoints)

    Syde Wearable Device is a digital sensor system used to objectively monitor motor function in children and adults, particularly in neuromuscular disorders. It continuously records movement data such as stride length, velocity, and limb activity during daily life. Specific endpoints, such as the Stride Velocity 95th Centile (SV95C), are derived from the recorded data. Higher values of SV95C indicate better motor performance, whereas lower values reflect greater functional impairment and a worse outcome.

  3. Improvement in dystonia as measured by the Burke-Fahn-Marsden Dystonia Rating Scale.

    Time frame: 5 years (multiple timepoints)

    The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) is a quantitative measure of dystonia severity used in both children and adults. A score of 0 indicates the absence of dystonia in all assessed body regions, whereas the maximum score of 120 reflects severe dystonia affecting all assessed body regions, even at rest.

  4. Improvement in spasticity as measured by the 13-item Spastic Paraplegia Rating Scale.

    Time frame: 5 years (multiple timepoints)

    The Spastic Paraplegia Rating Scale (SPRS) assesses functional impairment in children and adults with spastic paraplegia. A score of 0 indicates the absence of disease manifestation, whereas the maximum score of 52 reflects severe disease manifestation.

  5. Improvement in cognitive function as measured by the Bayley Scale of Infant Development 4.

    Time frame: 5 years (multiple timepoints)

    The Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4), is a standardized assessment used to evaluate developmental functioning in infants and young children across cognitive, language, and motor domains. Composite scores are standardized with a mean of 100 and a standard deviation of 15, typically ranging from 40 to 160. Higher scores indicate better developmental performance, while lower scores reflect increasing levels of developmental delay.

  6. Improvement in cognitive function as measured by the Vineland Adaptive Infant Behavior Scale 3.

    Time frame: 5 years (multiple timepoints)

    The Vineland Adaptive Behavior Scales, Third Edition (Vineland-3), is a standardized assessment that measures adaptive functioning in infants, children, and adults across communication, daily living skills, socialization, and motor domains. Adaptive Behavior Composite scores are standardized with a mean of 100 and a standard deviation of 15, typically ranging from 20 to 160. Higher scores indicate better adaptive functioning, whereas lower scores reflect greater impairment in adaptive behavior.

  7. Improvement in cognitive function as measured by the Wechsler Non-Verbal Intelligence Scale.

    Time frame: 5 years (multiple timepoints)

    The Wechsler Nonverbal Scale of Ability (WNV) is a standardized assessment of nonverbal cognitive functioning designed for children and adolescents, particularly those with language impairments. Scores are reported as a standard score with a mean of 100 and a standard deviation of 15, typically ranging from 40 to 160. Higher scores indicate better nonverbal intellectual ability, whereas lower scores reflect greater cognitive impairment.

  8. Improvement in communication as measured by the Vineland Adaptive Scale 3.

    Time frame: 5 years (multiple timepoints)

    The Vineland Adaptive Behavior Scales, Third Edition (Vineland-3), is a standardized assessment that measures adaptive functioning in infants, children, and adults across communication, daily living skills, socialization, and motor domains. Adaptive Behavior Composite scores are standardized with a mean of 100 and a standard deviation of 15, typically ranging from 20 to 160. Higher scores indicate better adaptive functioning, whereas lower scores reflect greater impairment in adaptive behavior.

  9. Behavioral Improvement measured by the Aberrant Behavior Checklist.

    Time frame: 5 years (multiple timepoints)

    The Aberrant Behavior Checklist (ABC) is a caregiver-reported assessment used to evaluate problem behaviors in children and adults with developmental and intellectual disabilities. It consists of five subscales (irritability, lethargy/social withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech) with a total score ranging from 0 to 174. A score of 0 indicates the absence of aberrant behaviors, whereas higher scores reflect increasing severity and frequency of behavioral problems.

  10. Behavioral Improvement measured by the M-CHAT or Autism Spectrum Quotient (depending on the participant's age).

    Time frame: 5 years (multiple timepoints)

    The Modified Checklist for Autism in Toddlers (M-CHAT) is a caregiver-completed screening tool used to identify children at risk for autism spectrum disorder. Scores range from 0 to 20, with lower scores indicating typical development and higher scores reflecting an increased risk for autism spectrum disorder and a worse outcome.

    The Autism-Spectrum Quotient (AQ) is a self-report questionnaire designed to measure the degree of autistic traits in children and adolescents. It consists of 50 items, yielding a total score ranging from 0 to 50. Lower scores indicate fewer autistic traits, whereas higher scores reflect a greater number of autistic traits.

  11. Improvement in sleep as measured by the Bruni Sleep Disturbance Scale.

    Time frame: 5 years (multiple timepoints)

    The Bruni Sleep Disturbance Scale for Children (SDSC) is a caregiver-reported questionnaire used to evaluate sleep disturbances in children. It consists of 26 items across six subscales, with a total score ranging from 26 to 130. Lower scores indicate fewer sleep problems, while higher scores reflect more severe sleep disturbances.

  12. Improvement in epilepsy as measured by seizure frequency.

    Time frame: 5 years (multiple timepoints)

  13. Improvement in Quality of Life as measured by Pediatric QOL Inventory - Family and Core module (age appropriate).

    Time frame: 5 years (multiple timepoints)

    The Pediatric Quality of Life Inventory (PedsQL) Core and Family Impact Modules are standardized questionnaires used to assess health-related quality of life in children and the impact of pediatric health conditions on family functioning. Scores are transformed to a 0-100 scale, where 0 represents the poorest quality of life and 100 represents the best possible quality of life.

Study contacts

Contact information is provided by the study sponsor or research team.

Damjan Osredkar, MD, PhD

CONTACT

[email protected]

0038615229273

Nina Žakelj, MD

CONTACT

[email protected]

0038640367144

Sponsors and collaborators

Lead sponsor

CTNNB1 Foundation

Other

Collaborators

  • University Medical Centre Ljubljana

Registry information

Official study title

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

Acronym: GAIN-CTNNB1

Important dates

Study start
2025
Primary completion
2032
Study completion
2032
First posted
Dec 8, 2025
Registry last updated
Mar 25, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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