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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
12
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.
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.
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.
University Medical Centre Ljubljana
Ljubljana, Slovenia
RECRUITINGIncidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Monitoring for treatment-emergent adverse events and serious adverse events in all participants.
Time frame: 5 years (multiple timepoints)
Improvement in motor function as measured by the Bayley Scale of Infant Development 4.
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.
Time frame: 5 years (multiple timepoints)
Improvement in motor function as measured by the Wearable Syde Device (in ambulant patients).
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.
Time frame: 5 years (multiple timepoints)
Improvement in dystonia as measured by the Burke-Fahn-Marsden Dystonia Rating Scale.
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.
Time frame: 5 years (multiple timepoints)
Improvement in spasticity as measured by the 13-item Spastic Paraplegia Rating Scale.
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.
Time frame: 5 years (multiple timepoints)
Improvement in cognitive function as measured by the Bayley Scale of Infant Development 4.
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.
Time frame: 5 years (multiple timepoints)
Improvement in cognitive function as measured by the Vineland Adaptive Infant Behavior Scale 3.
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.
Time frame: 5 years (multiple timepoints)
Improvement in cognitive function as measured by the Wechsler Non-Verbal Intelligence Scale.
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.
Time frame: 5 years (multiple timepoints)
Improvement in communication as measured by the Vineland Adaptive Scale 3.
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.
Time frame: 5 years (multiple timepoints)
Behavioral Improvement measured by the Aberrant Behavior Checklist.
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.
Time frame: 5 years (multiple timepoints)
Behavioral Improvement measured by the M-CHAT or Autism Spectrum Quotient (depending on the participant's age).
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.
Time frame: 5 years (multiple timepoints)
Improvement in sleep as measured by the Bruni Sleep Disturbance Scale.
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.
Time frame: 5 years (multiple timepoints)
Improvement in epilepsy as measured by seizure frequency.
Time frame: 5 years (multiple timepoints)
Improvement in Quality of Life as measured by Pediatric QOL Inventory - Family and Core module (age appropriate).
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.
Time frame: 5 years (multiple timepoints)
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