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Targeting of C-ROS-1 Activity Using a Controlled Release Carrier to Treat Craniosynostosis in a Preclinical Model of
Esther Camp1,2, Laura Gonzalez Garcia3, Clara Pribadi1,2
1Mesenchymal Stem Cell Laboratory, School of Biomedicine, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia.
Abstract:
Saethre-Chotzen syndrome (SCS) is one of the most prevalent craniosynostosis, caused by a loss-of-function mutation in the TWIST-1 gene, with current treatment options relying on major invasive transcranial surgery. TWIST-1 haploinsufficient osteogenic progenitor cells exhibit increased osteogenic differentiation potential due to an upregulation of the transmembrane tyrosine kinase receptor, C-ROS-1, a TWIST-1 target gene known to promote bone formation. The present study assessed the efficacy of suppressing C-ROS-1 activity using a known chemical inhibitor to C-ROS-1, crizotinib, to halt premature coronal suture fusion in a preclinical mouse model of SCS. Crizotinib (1 μM, 2 μM, or 4 μM) was administered locally over the calvaria of Twist-1del/+ heterozygous mice prior to coronal suture fusion using either a nonresorbable collagen sponge (quick drug release) or a resorbable sodium carboxymethylcellulose microdisk (slow sustained release). Coronal suture fusion rates and bone parameters were determined by μCT imaging and histomorphometric analysis of calvaria postcoronal suture fusion. Results demonstrated a dose-dependent increase in the efficacy of crizotinib to maintain coronal suture patency, with no adverse effects to brain, kidney, liver, and spleen tissue, or blood cell parameters. Moreover, crizotinib delivered on microdisks resulted in a greater efficacy at a lower concentration to reduce bone formation at the coronal suture sites compared to sponges. However, the bone inhibitory effects were found to be diminished by over time following cessation of treatment. Our findings lay the foundation for the development of a pharmacological nonsurgical, targeted approach to temporarily maintain open coronal sutures in SCS patients. This study could potentially be used to develop similar therapeutic strategies to treat different syndromic craniosynostosis conditions caused by known genetic mutations.
Insights
Crizotinib effectively prevents premature coronal suture fusion in a Saethre-Chotzen syndrome mouse model by inhibiting C-ROS-1. This offers a potential non-surgical treatment for craniosynostosis.
Area of Science:
- Genetics and Developmental Biology
- Pharmacology and Therapeutics
- Craniofacial Surgery and Orthodontics
Background:
- Saethre-Chotzen syndrome (SCS) is a craniosynostosis caused by TWIST-1 mutations, currently treated with invasive surgery.
- TWIST-1 haploinsufficiency increases osteogenic progenitor cell differentiation via C-ROS-1 upregulation, promoting bone formation.
- Targeting C-ROS-1 offers a potential therapeutic strategy to counteract premature suture fusion in SCS.
Purpose of the Study:
- To evaluate the efficacy of crizotinib, a C-ROS-1 inhibitor, in preventing premature coronal suture fusion in a mouse model of SCS.
- To assess the impact of different drug delivery methods (collagen sponge vs. carboxymethylcellulose microdisk) on crizotinib's effectiveness.
- To determine the safety profile of local crizotinib administration.
Main Methods:
- Local administration of crizotinib (1-4 μM) to the calvaria of Twist-1 heterozygous mice using collagen sponges or carboxymethylcellulose microdisks.
- Assessment of coronal suture fusion rates and bone parameters using micro-CT imaging and histomorphometric analysis.
- Evaluation of potential adverse effects on brain, kidney, liver, spleen, and blood cell parameters.
Main Results:
- Crizotinib demonstrated a dose-dependent efficacy in maintaining coronal suture patency.
- Microdisk delivery of crizotinib was more effective at lower concentrations than sponge delivery in reducing bone formation.
- No adverse effects were observed in major organs or blood cell parameters, indicating a favorable safety profile.
Conclusions:
- Crizotinib is a promising pharmacological agent for a non-surgical approach to temporarily maintain coronal suture patency in SCS.
- The study provides a foundation for developing targeted therapies for syndromic craniosynostosis.
- Further research is warranted to explore sustained drug delivery and long-term efficacy.
