emmm.201708492.pdf (3.56 MB)
Efficacy of systemic temozolomide-activated phage-targeted gene therapy in human glioblastoma
journal contribution
posted on 2023-06-09, 21:06 authored by Justyna Magdalena Przystal, Sajee Waramit, Md Zahidul Islam Pranjol, Wenqing Yan, Grace Chu, Aitthiphon Chongchai, Nagore Gene Olaciregui, Ghazaleh Tabatabai, Angel Montero Carcaboso, Eric Ofori Aboagye, Keittisak Suwan, Amin Hajitoulioblastoma 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 avß3 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.
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- Published
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- Published version
Journal
EMBO Molecular MedicineISSN
1757-4676Publisher
WileyExternal DOI
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4Volume
11Article number
a8492Department affiliated with
- Biochemistry Publications
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- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2020-04-17First Open Access (FOA) Date
2020-04-17First Compliant Deposit (FCD) Date
2020-04-16Usage metrics
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