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Title: Bacteriophage : from bacteria to targeted gene delivery to mammalian cells
Author: Yata, Teerapong
ISNI:       0000 0004 5361 3062
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Bacteriophage (phage), bacterial viruses, have been improved as non-human pathogenic viral vectors for the purpose of introducing genetic materials into mammalian cells. Previously, our group generated a novel Adeno-associated virus/Phage (AAVP) hybrid vector as a valuable tool for targeted gene transfer to mammalian cells. However, the efficacy of bacteriophage-based vectors is considered relatively poor, meaning that ways of improving it are of considerable interest. First approach to improve AAVP-mediated gene delivery is through chemical modification. We showed that the transduction efficiency of AAVP was increased by the complexation of phage vectors with cationic molecules and calcium phosphate co-precipitation. Application of the bacteriophage complex carrying a cytotoxic gene resulted in eradication of cultured brain tumour cells. The chemically modified vector showed superior gene delivery over the conventional vector and can thus be regarded as an improved version of phage-based vector that has promise in cancer gene therapy. Next, we demonstrated that Extracellular Matrix (ECM) presents an obstacle for AAVP. Using brain cancer cell lines as a model, AAVP transduction was significantly increased by collagenase and hyaluronidase-mediated degradation of ECM, which can subsequently be translated into tumour cell eradication through AAVP-mediated gene therapy. Our findings prove that combination of AAVP vectors with ECM depletion represents a powerful strategy to advance phage- guided gene transfer. Finally, we engineered the prototype bacteriophage-based multifunctional vector as a proof-of-concept model that can simultaneously display three different peptides and carry a mammalian transgene cassette. Our results show that bacteriophage can be used as a scaffold for constructing multifunctional carriers that integrate multiple functions, which may have great potential for gene delivery applications. Together, the data demonstrate the potential for improved AAVP-based gene transfer to mammalian cells focusing on the use of chemical modification, manipulation of ECM, and the generation of multifunctional phage vectors.
Supervisor: Hajitou, Amin Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available