The Combination of Vascular Endothelial Growth Factor A (VEGF-A) and Fibroblast Growth Factor 1 (FGF1) Modified mRNA Improves Wound Healing in Diabetic Mice: An Ex Vivo and In Vivo Investigation

Author:

Tejedor Sandra12ORCID,Wågberg Maria1ORCID,Correia Cláudia1,Åvall Karin1,Hölttä Mikko1ORCID,Hultin Leif3,Lerche Michael4,Davies Nigel4ORCID,Bergenhem Nils5,Snijder Arjan6ORCID,Marlow Tom6,Dönnes Pierre27,Fritsche-Danielson Regina1,Synnergren Jane28,Jennbacken Karin1ORCID,Hansson Kenny1

Affiliation:

1. Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, 431 50 Gothenburg, Sweden

2. Systems Biology Research Center, School of Bioscience, University of Skövde, 541 28 Skövde, Sweden

3. Imaging and Data Analytics, Clinical and Pharmacological Safety Science, BioPharmaceuticals R&D, AstraZeneca, 431 50 Gothenburg, Sweden

4. Advanced Drug Delivery, Pharmaceutical Science, BioPharmaceuticals R&D, AstraZeneca, 431 50 Gothenburg, Sweden

5. Alliance Management, Business Development and Licensing, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA 02451, USA

6. Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, 431 50 Gothenburg, Sweden

7. SciCross AB, 541 35 Skövde, Sweden

8. Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden

Abstract

Background: Diabetic foot ulcers (DFU) pose a significant health risk in diabetic patients, with insufficient revascularization during wound healing being the primary cause. This study aimed to assess microvessel sprouting and wound healing capabilities using vascular endothelial growth factor (VEGF-A) and a modified fibroblast growth factor (FGF1). Methods: An ex vivo aortic ring rodent model and an in vivo wound healing model in diabetic mice were employed to evaluate the microvessel sprouting and wound healing capabilities of VEGF-A and a modified FGF1 both as monotherapies and in combination. Results: The combination of VEGF-A and FGF1 demonstrated increased vascular sprouting in the ex vivo mouse aortic ring model, and topical administration of a combination of VEGF-A and FGF1 mRNAs formulated in lipid nanoparticles (LNPs) in mouse skin wounds promoted faster wound closure and increased neovascularization seven days post-surgical wound creation. RNA-sequencing analysis of skin samples at day three post-wound creation revealed a strong transcriptional response of the wound healing process, with the combined treatment showing significant enrichment of genes linked to skin growth. Conclusion: f-LNPs encapsulating VEGF-A and FGF1 mRNAs present a promising approach to improving the scarring process in DFU.

Funder

Swedish Knowledge Foundation

Publisher

MDPI AG

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