ASO Treatment for Syndromic Craniosynostoses (NAUTILUS)

Nano-ink Based Antisense oligonUcleoTIde deLivery for Ultra-personaIized Treatment of Syndromic Craniosynostoses

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Crouzon Syndrome; Pfeiffer Syndrome; Craniosynostoses; Muenke Syndrome; Saethre Chotzen Syndrome; Apert Syndrome
• Intervention / Treatment: Genetic: Design of patient specific ASO

• Study Type: Observational
• Enrollment (Estimated): 12

Contacts and Locations

• Study Contact: Name: Wanda Lattanzi; Phone Number: +390630156946; Email: wanda.lattanzi@unicatt.it

Study Locations

• France
  • Paris, France
    • Institut Imagine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

• 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.

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nano-ink development	Formulation of hydrogel-based nano-ink embedded with functionalized PLGA-PEG-bis-sulfone (PPB) NPs able to deliver and release of therapeutic ASOs.	16 months
In vivo validation	Validation of ASO efficiency in murine model tissue	16 months

Collaborators and Investigators

• Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Investigators: Principal Investigator: Wanda Lattanzi, Fondazione Policlinico Universitario A. Gemelli, IRCCS

Study record dates

Study Major Dates

• Study Start (Estimated): April 20, 2026
• Primary Completion (Estimated): April 20, 2027
• Study Completion (Estimated): April 20, 2028

Study Registration Dates

• First Submitted: April 10, 2026
• First Submitted That Met QC Criteria: April 10, 2026
• First Posted (Actual): April 17, 2026

Study Record Updates

• Last Update Posted (Actual): April 17, 2026
• Last Update Submitted That Met QC Criteria: April 10, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bone Diseases; Musculoskeletal Diseases; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Congenital Abnormalities; Bone Diseases, Developmental; Limb Deformities, Congenital; Synostosis; Dysostoses; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Syndactyly; Craniosynostoses; Acrocephalosyndactylia; Craniofacial Dysostosis; Muenke Syndrome
• Other Study ID Numbers: 26984

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No