ASO Treatment for Syndromic Craniosynostoses

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Conditions studied: Craniosynostoses, Crouzon Syndrome, Saethre Chotzen Syndrome, Muenke Syndrome, Pfeiffer Syndrome, Apert Syndrome

In brief

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.

Key facts

Study ID

NCT07535372

Run by

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

People needed

12

Starts

2026-04-20

Expected to finish

2028-04-20

Last updated by the study team

2026-04-17

Who can join

Age: any, up to 5. Sex: any. Healthy volunteers: not accepted.

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.

Where it is running

• Institut Imagine — Paris, France

Full record on ClinicalTrials.gov

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