AFM TELETHON #23607 - ROCKET - Personalized non-invasive nanotherapy of Crouzon syndrome through FGFR2 gene knock-down by recombinant human ferritin-based targeted siRNA delivery (DSB.AD006.336)

Thematic area

Biomedical sciences

Project area

Structure responsible for the research project

Institute of molecular biology and pathology (IBPM)

Project manager

ELISABETTA FALVO
Phone number: 0649910990
Email: elisabetta.falvo@cnr.it

Abstract

Crouzon syndrome (CS) is a rare genetic syndrome (1:60.000 newborns) presenting with complex craniofacial malformations, mainly due to the premature ossification of skull sutures that causes a rapidly progressing skull constraint. CS is autosomal dominant with variable expressivity, occurring as a mild or severe form of syndromic multi-suture craniosynostosis, caused by missense Gain-Of-Function mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2) gene, resulting in the constitutive activation of receptor signaling. To date, the standard treatment is highly invasive, involving surgical cranial vault remodeling, usually performed by 1 year of age to release the constraint and consequent brain damage, followed by additional maxillofacial surgeries. The project aims to develop a personalized gene therapy based on allele-specific siRNAs targeting the mutant FGFR2. This knock-down technology will be selectively delivered in patient suture cells undergoing osteogenic differentiation through a recombinant human ferritin-based nanocarrier. This strategy is intended to hamper the overactive FGFR-induced osteogenesis only in the pathological suture cells of Crouzon patients' s skull.

Goals

The main objective of ROCKET is to develop an innovative targeted and stimuli-responsive delivery strategy to correct the genetic defect causing Crouzon syndrome (CS), a paradigm of syndromic craniosynostosis. This will enable achieving a personalized therapy for CS able to replace and reduce the invasiveness of multiple surgical procedures, preventing the risk for relapses and the associated morbidities.
The HFt-siRNA constructs will be developed and functionally validated in vitro (on patients' cells) during the first year and tested in preclinical setting (murine model) during the second year, paving the way for subsequent clinical translation in phase I clinical trials.

Start date of activity

01/08/2021

Keywords

FGFR2 pathway, Crouzon syndrome, Recombinant human ferritin

Last update: 05/07/2025