Highly versatile cell-penetrating peptide loaded scaffold for efficient and localised gene delivery to multiple cell types: From development to application in tissue engineering

Raftery, Rosanne M.; Walsh, David P.; Blokpoel Ferreras, Lia; Mencía Castaño, Irene; Chen, Gang; LeMoine, Mark; Osman, Gizem; Shakesheff, Kevin M.; Dixon, James E.; O'Brien, Fergal J.

Abstract

Gene therapy has recently come of age with seven viral vector-based therapies gaining regulatory approval in recent years. In tissue engineering, non-viral vectors are preferred over viral vectors, however, lower transfection efficiencies and difficulties with delivery remain major limitations hampering clinical translation. This study describes the development of a novel multi-domain cell-penetrating peptide, GET, designed to enhance cell interaction and intracellular translocation of nucleic acids; combined with a series of porous collagen-based scaffolds with proven regenerative potential for different indications. GET was capable of transfecting cell types from all three germ layers, including stem cells, with an efficiency comparable to Lipofectamine® 3000, without inducing cytotoxicity. When implanted in vivo, GET gene-activated scaffolds allowed for host cell infiltration, transfection localized to the implantation site and sustained, but transient, changes in gene expression – demonstrating both the efficacy and safety of the approach. Finally, GET carrying osteogenic (pBMP-2) and angiogenic (pVEGF) genes were incorporated into collagen-hydroxyapatite scaffolds and with a single 2μg dose of therapeutic pDNA, induced complete repair of critical-sized bone defects within 4 weeks. GET represents an exciting development in gene therapy and by combining it with a scaffold-based delivery system offers tissue engineering solutions for a myriad of regenerative indications.

Citation

Raftery, R. M., Walsh, D. P., Blokpoel Ferreras, L., Mencía Castaño, I., Chen, G., LeMoine, M., …O'Brien, F. J. (2019). Highly versatile cell-penetrating peptide loaded scaffold for efficient and localised gene delivery to multiple cell types: From development to application in tissue engineering. Biomaterials, 216, Article 119277. https://doi.org/10.1016/j.biomaterials.2019.119277

• Journal Article Type: Article
• Acceptance Date: Jun 10, 2019
• Online Publication Date: Jun 13, 2019
• Publication Date: 2019-09
• Deposit Date: Jul 16, 2019
• Publicly Available Date: Jun 14, 2020
• Journal: Biomaterials
• Print ISSN: 0142-9612
• Electronic ISSN: 1878-5905
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 216
• Article Number: 119277
• DOI: https://doi.org/10.1016/j.biomaterials.2019.119277
• Keywords: GET; Gene delivery; Cell-penetrating peptide; Tissue engineering; Bone regeneration
• Public URL: https://nottingham-repository.worktribe.com/output/2298644
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S014296121930376X?via%3Dihub
• Additional Information: This article is maintained by: Elsevier; Article Title: Highly versatile cell-penetrating peptide loaded scaffold for efficient and localised gene delivery to multiple cell types: From development to application in tissue engineering; Journal Title: Biomaterials; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.biomaterials.2019.119277; Content Type: article; Copyright: © 2019 Elsevier Ltd. All rights reserved.
• Contract Date: Jul 16, 2019