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

NCT07270549 | Recruiting Phase 1 DMC

• 2 other identifiers: 0120-536/2025-27112025-522719-40-00
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

CTNNB1 Neurodevelopmental Syndrome

Keywords

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

Outcome Measures

Primary Outcomes (1)

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

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

  5 years (multiple timepoints)

Secondary Outcomes (13)

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

  5 years (multiple timepoints)

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

  5 years (multiple timepoints)

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

  5 years (multiple timepoints)

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

  5 years (multiple timepoints)

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

  5 years (multiple timepoints)

Study Arms (1)

Treatment arm

EXPERIMENTAL

Urbagen, an AAV-9 mediated gene addition therapy

Biological: Urbagen gene addition therapy; Drug: Sirolimus; Drug: Methylprednisolone (Corticosteroid)

Interventions

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.

Treatment arm

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.

Treatment arm

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.

Treatment arm

Eligibility Criteria

• Age: 2 Years - 12 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify 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).
• 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.

You may not qualify 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 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.

Sponsors & Collaborators

• CTNNB1 Foundation: lead
• University Medical Centre Ljubljana: collaborator

Study Sites (1)

University Medical Centre Ljubljana

Ljubljana, 1000, Slovenia

RECRUITING

Related Publications (6)

• Zakelj N, Gosar D, Mirosevic S, Sanders SJ, Ljungdahl A, Kohani S, Huang S, Leong LI, An Y, Teo MJ, Moultrie F, Jerala R, Lainscek D, Forstneric V, Susjan P, Lisowski L, Perez-Iturralde A, Mrak JO, Chan HYE, Osredkar D. Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome. HGG Adv. 2025 Oct 9;6(4):100483. doi: 10.1016/j.xhgg.2025.100483. Epub 2025 Jul 18.

  PMID: 40684264 BACKGROUND

• Mirosevic S, Khandelwal S, Amerson E, Parks E, Parks M, Cochran L, Gonzalez Hernandez A, Ferraro M, Lisowski L, Perez-Iturralde A, Chung W, Jacob MH, Zakelj N, Lainscek D, Forstneric V, Susjan P, Maruna M, Jerala R, Osredkar D. Paving the way toward treatment solutions for CTNNB1 syndrome: a patient organization perspective. Ther Adv Rare Dis. 2025 Feb 12;6:26330040251318355. doi: 10.1177/26330040251318355. eCollection 2025 Jan-Dec.

  PMID: 39949392 BACKGROUND

• Mirosevic S, Khandelwal S, Susjan P, Zakelj N, Gosar D, Forstneric V, Lainscek D, Jerala R, Osredkar D. Correlation between Phenotype and Genotype in CTNNB1 Syndrome: A Systematic Review of the Literature. Int J Mol Sci. 2022 Oct 19;23(20):12564. doi: 10.3390/ijms232012564.

  PMID: 36293418 BACKGROUND

• Parichha A, Datta D, Singh A, Talwar I, Yadav S, Bose M, Suresh V, Mirosevic S, Zakelj N, Gosar D, Osredkar D, Tole S. An evolutionarily conserved role for CTNNB1/beta-CATENIN in regulating the development of the corpus callosum. iScience. 2025 Aug 9;28(9):113335. doi: 10.1016/j.isci.2025.113335. eCollection 2025 Sep 19.

  PMID: 40894864 BACKGROUND

• Arkar Silan U, Trebse A, Kovac J, Rogac M, Troha Gergeli A, Sket R, Bregant T, Neubauer D, Peterlin B, Osredkar D. Unravelling genetic etiology of cerebral palsy: findings from a Slovenian pediatric cohort. Front Neurol. 2025 Jul 23;16:1615449. doi: 10.3389/fneur.2025.1615449. eCollection 2025.

  PMID: 40771987 BACKGROUND

• Groselj U, Kavcic M, Drole Torkar A, Kafol J, Lainscek D, Jerala R, Sever M, Zver S, Sersa G, Cemazar M, Strojan P, Groselj A, Zerjav Tansek M, Mirosevic S, Ivancan S, Prelog T, Gosar D, Orazem Mrak J, Mlinaric M, Bertok S, Kovac J, Kodric J, Battelino S, Pokorn M, Ihan A, Jazbec J, Battelino T, Osredkar D. Gene therapy of rare diseases as a milestone in medicine - overview of the field and report on initial experiences in Slovenia. Orphanet J Rare Dis. 2025 Jun 5;20(1):279. doi: 10.1186/s13023-025-03828-8.

  PMID: 40474241 BACKGROUND

Related Links

• CTNNB1 Foundation

MeSH Terms

Interventions

Sirolimus; Methylprednisolone; Adrenal Cortex Hormones

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Central Study Contacts

Damjan Osredkar, MD, PhD

CONTACT

0038615229273; gain@ctnnb1-foundation.org

Nina Žakelj, MD

CONTACT

0038640367144; gain@ctnnb1-foundation.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Damjan Osredkar, MD, PhD

Study Record Dates

• First Submitted: November 14, 2025
• First Posted: December 8, 2025
• Study Start: November 1, 2025
• Primary Completion (Estimated): December 31, 2032
• Study Completion (Estimated): December 31, 2032
• Last Updated: March 25, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

SL (1)