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
RECRUITINGAssesing safety and tolerability of Urbagen.
Monitoring for any 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.
Time frame: 5 years (multiple timepoints)
Improvement in motor function as measured by the Wearable Syde Device (in ambulant patients).
Time frame: 5 years (multiple timepoints)
Improvement in dystonia as measured by the Burke-Fahn-Marsden Dystonia Rating Scale.
Time frame: 5 years (multiple timepoints)
Improvement in spasticity as measured by the 13-item Spastic Paraplegia Rating Scale.
Time frame: 5 years (multiple timepoints)
Improvement in cognitive function as measured by the Bayley Scale of Infant Development 4.
Time frame: 5 years (multiple timepoints)
Improvement in cognitive function as measured by the Vineland Adaptive Infant Behavior Scale 3.
Time frame: 5 years (multiple timepoints)
Improvement in cognitive function as measured by the Wechsler Non-Verbal Intelligence Scale.
Time frame: 5 years (multiple timepoints)
Improvement in communication as measured by the Vineland Adaptive Scale 3.
Time frame: 5 years (multiple timepoints)
Behavioral Improvement measured by the Aberrant Behavior Checklist.
Time frame: 5 years (multiple timepoints)
Behavioral Improvement measured by the M-CHAT or Autism Spectrum Quotient (depending on the participant's age).
Time frame: 5 years (multiple timepoints)
Improvement in sleep as measured by the Bruni Sleep Disturbance Scale.
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).
Time frame: 5 years (multiple timepoints)
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