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.
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.
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.
Single group
Urbagen gene addition therapy
Biological/VaccineUrbagen 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
DrugThe 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)
DrugThe 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.
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Monitoring for treatment-emergent adverse events and serious adverse events in all participants.
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.
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.
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.
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.
Click on the lead sponsor to view all of their trials.
CTNNB1 Foundation
Lead sponsor
University Medical Centre Ljubljana
Sponsor institution
University Medical Centre Ljubljana
Collaborator
