Targeted allele-specific FGFR2 knockdown via human recombinant ferritin nanoparticles for personalized treatment of Crouzon syndrome

Targeted allele-specific FGFR2 knockdown via human recombinant ferritin nanoparticles for personalized treatment of Crouzon syndrome

Crouzon syndrome is a rare genetic craniofacial malformation caused by heterozygous gain-of-function mutations in the FGFR2 gene. The resulting constitutive activation of the FGFR2 signaling causes the premature osteogenic differentiation of calvarial mesenchymal stromal cells in skull sutures, lead...

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Main Authors: Federica Tiberio, Martina Salvati, Luca Polito, Giada Tisci, Alessia Vita, Ornella Parolini, Luca Massimi, Lorena Di Pietro, Pierpaolo Ceci, Gianpiero Tamburrini, Alessandro Arcovito, Elisabetta Falvo, Wanda Lattanzi
Format: Article
Language:English
Published: Elsevier 2025-03-01
Series:Molecular Therapy: Nucleic Acids
Subjects:
MT: Oligonucleotides: Therapies and Applications
craniosynostosis
Crouzon syndrome
small interfering RNA
ferritin nanoparticles
gene silencing
Online Access:http://www.sciencedirect.com/science/article/pii/S2162253124003147
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Summary:Crouzon syndrome is a rare genetic craniofacial malformation caused by heterozygous gain-of-function mutations in the FGFR2 gene. The resulting constitutive activation of the FGFR2 signaling causes the premature osteogenic differentiation of calvarial mesenchymal stromal cells in skull sutures, leading to early suture ossification. Craniectomy is the gold standard treatment, being invasive and burdened by complications. To address these issues, we developed personalized allele-specific (AS) small interfering RNA (siRNA) to knockdown the expression of the FGFR2 mutant allele in Crouzon patient-derived suture cells. The selected therapeutic siRNA mitigated FGFR2 cascade downregulating phosphorylation of FGFR2 (48%) and of its key effector ERK1/2 (77%) as RUNX2 protein levels (34%). This effect was confirmed by the reduced osteogenic commitment and differentiation of treated cells, evidenced by decreased expression of osteogenic marker genes and a 5-fold decrease in mineralized matrix deposition. We developed a highly biocompatible delivery system for siRNAs, based on human recombinant ferritin nanoparticles (NPs), combining cell targeting with improved nucleic acid encapsulation and endosomal escape properties. We demonstrated the ability of these NPs to deliver and release siRNAs within target cells, sustaining their inhibitory and AS effects. Here, we show that ferritin-mediated AS FGFR2 knockdown by siRNA represents a suitable strategy to dampen FGFR2 overactivation in patients’ cells.
ISSN:2162-2531

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