Efficacy of systemic temozolomide‐activated phage‐targeted gene therapy in human glioblastoma

Przystal, Justyna Magdalena, Waramit, Sajee, Pranjol, Md Zahidul Islam, Yan, Wenqing, Chu, Grace, Chongchai, Aitthiphon, Olaciregui, Nagore Gene, Tabatabai, Ghazaleh, Carcaboso, Angel Montero, Aboagye, Eric Ofori, Suwan, Keittisak and Hajitou, Amin (2019) Efficacy of systemic temozolomide‐activated phage‐targeted gene therapy in human glioblastoma. EMBO Molecular Medicine, 11 (4). a8492. ISSN 1757-4676

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Abstract

lioblastoma multiforme (GBM) is the most lethal primary intracranial malignant neoplasm in adults and most resistant to treatment. Integration of gene therapy and chemotherapy, chemovirotherapy, has the potential to improve treatment. We have introduced an intravenous bacteriophage (phage) vector for dual targeting of therapeutic genes to glioblastoma. It is a hybrid AAV/phage, AAVP, designed to deliver a recombinant adeno‐associated virus genome (rAAV) by the capsid of M13 phage. In this vector, dual tumor targeting is first achieved by phage capsid display of the RGD4C ligand that binds the αvβ3 integrin receptor. Second, genes are expressed from a tumor‐activated and temozolomide (TMZ)‐induced promoter of the glucose‐regulated protein, Grp78. Here, we investigated systemic combination therapy using TMZ and targeted suicide gene therapy by the RGD4C/AAVP‐Grp78. Firstly, in vitro we showed that TMZ increases endogenous Grp78 gene expression and boosts transgene expression from the RGD4C/AAVP‐Grp78 in human GBM cells. Next, RGD4C/AAVP‐Grp78 targets intracranial tumors in mice following intravenous administration. Finally, combination of TMZ and RGD4C/AAVP‐Grp78 targeted gene therapy exerts a synergistic effect to suppress growth of orthotopic glioblastoma.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 17 Apr 2020 06:43
Last Modified: 17 Apr 2020 07:00
URI: http://sro.sussex.ac.uk/id/eprint/90830

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