ASO Treatment for Syndromic Craniosynostoses

NCT07535372 | Not Yet Recruiting

• 1 other identifier: 26984
• Study Type: observational
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

Syndromic craniosynostoses (SCS) are rare genetic disorders defined by premature cranial suture fusion, resulting in abnormal craniofacial development and constrained brain growth. These conditions, including Muenke, Saethre-Chotzen, Crouzon, Apert, Pfeiffer and craniofrontonasal syndromes, are typically caused by gain- or loss-of-function variants in key regulators of suture biology such as FGFR1/2/3, TWIST1 and TCF12. Current management is exclusively surgical, relying on early cranial vault remodelling and subsequent reconstructive procedures, which carry substantial risks (e.g. blood loss, infection, re-synostosis) and do not address the underlying molecular etiology. Recent advances in RNA-based therapeutics have demonstrated the potential of mutation-specific approaches to normalize aberrant osteogenic differentiation in patient-derived cells. However, clinical translation remains limited by inefficient delivery and lack of sustained therapeutic activity. The NAUTILUS project aims to overcome these barriers by developing a non-invasive, ultra-personalized therapeutic platform based on mutation-specific antisense oligonucleotides (ASOs) delivered via a nano-engineered system. The project will design and validate patient-tailored ASOs targeting the molecular drivers of SCS, with the goal of either silencing pathogenic gain-of-function alleles or restoring physiological expression in loss-of-function contexts. Functional efficacy will be assessed in patient-derived cellular models by evaluating transcript modulation and rescue of protein function. In parallel, NAUTILUS will optimize a nano-ink delivery platform combining PLGA-PEG-bis-sulfone nanoparticles with a GelMA-based hydrogel scaffold, enabling localized, controlled, and sustained ASO release within the cranial suture niche. Preclinical validation in relevant mouse models will assess the capacity of this platform to delay or prevent pathological suture ossification, ultimately reducing the need for repeated surgical interventions. By directly targeting the genetic basis of disease, NAUTILUS proposes a transformative approach to SCS management. This strategy has the potential to decrease treatment invasiveness, improve clinical outcomes, and enhance quality of life, establishing a precision medicine paradigm for rare craniofacial disorders.

Conditions

Craniosynostoses; Crouzon Syndrome; Saethre Chotzen Syndrome; Muenke Syndrome; Pfeiffer Syndrome; Apert Syndrome

Outcome Measures

Primary Outcomes (1)

• ASO design and development

  Development of personalized therapeutic ASOs to restore the expression/function of disease-causing genes in patient-derived suture cells.

  12 months

Secondary Outcomes (2)

• Nano-ink development

  16 months

• In vivo validation

  16 months

Interventions

Design of patient specific ASO GENETIC

For each patient enrolled cranial suture tissue waste and peripheral blood sample will be collected for cell isolation and ASO in vitro testing

Eligibility Criteria

• Age: Up to 5 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)
• Sampling Method: Non-Probability Sample

Study Population

Prospective and retrospective paediatric patients, undergoing/underwent corrective surgery for craniosynostosis as per standard of care, will be enrolled at Policlinico Gemelli upon obtain a written informed consent by their parents/legal guardians. Patient selection will be based on genetic evaluations from prior testing conducted as part of their clinical management. A total of 12 patients, with confirmed genetic diagnosis of SCS, with at least 4 different disease-causing mutations, will be selected for the study and cells isolated from their suture samples (surgical waste) analysed.

You may qualify if:

• Paediatric patients (0-5 years), with a confirmed genetic diagnosis of syndromic craniosynostosis involving pathogenic GoF or LoF variants in FGFR1-3, TWIST1, TCF12, EFNB1, ERF, MSX2, or ALX4.
• Availability of cranial-suture tissue fragments obtained during surgical remodelling procedures and classified as surgical waste.
• Signed informed consent from parents or legal guardians.

You may not qualify if:

• Patients older than 5 years.
• Patients aged 0-5 years with conditions unrelated to syndromic craniosynostosis in the selected genes.
• Genetic variants of uncertain significance or undetermined molecular diagnosis.
• Tissue samples with insufficient quantity or inadequate quality for cell isolation or culture.
• Refusal of informed consent.

Sponsors & Collaborators

• Fondazione Policlinico Universitario Agostino Gemelli IRCCS: lead

Study Sites (1)

Institut Imagine

Paris, France

Location

MeSH Terms

Conditions

Craniosynostoses; Craniofacial Dysostosis; Acrocephalosyndactylia; Muenke Syndrome

Condition Hierarchy (Ancestors)

Synostosis; Dysostoses; Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Syndactyly; Limb Deformities, Congenital

Study Officials

• Wanda Lattanzi

  Fondazione Policlinico Universitario A. Gemelli, IRCCS

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Wanda Lattanzi

CONTACT

+390630156946; wanda.lattanzi@unicatt.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 10, 2026
• First Posted: April 17, 2026
• Study Start: April 20, 2026
• Primary Completion (Estimated): April 20, 2027
• Study Completion (Estimated): April 20, 2028
• Last Updated: April 17, 2026

Record last verified: 2026-04

Locations

FR (1)