Hybrid prokaryotic-eukaryotic vectors for targeted gene delivery to brain tumours in animal models
Lead Research Organisation:
Imperial College London
Department Name: Dept of Medicine
Abstract
We aim to develop a novel strategy for the treatment of human glioblastomas. These brain tumours are one of the most lethal malignancies. Despite progress in neurosurgery, radiation and chemotherapy, little progress has been made in the treatment of these tumours. Therefore, new therapeutic strategies are urgently needed.
Gene therapy is an attractive approach for cancer treatment. Glioblastomas were one of the earliest targets of cancer gene therapy, but the first clinical trials were not successful because of the inefficient delivery of therapeutic genes into the tumours. Thus, there is a need to develop new vector systems that are safe and able to provide strong expression of the therapeutic genes within the tumours. To achieve these two goals, these vectors need to be specifically targeted to the tumour tissue.
We have recently showed that combination of attributes of various viruses resulted in the generation of hybrid viral vectors for efficient and targeted systemic gene therapy. We will use this strategy to generate a novel hybrid vector for targeted delivery of therapeutic genes to glioblastoma.
These approaches could result in the derivation of a targeted vector system which would represent a major advance in the management and therapy of human glioblastoma.
Gene therapy is an attractive approach for cancer treatment. Glioblastomas were one of the earliest targets of cancer gene therapy, but the first clinical trials were not successful because of the inefficient delivery of therapeutic genes into the tumours. Thus, there is a need to develop new vector systems that are safe and able to provide strong expression of the therapeutic genes within the tumours. To achieve these two goals, these vectors need to be specifically targeted to the tumour tissue.
We have recently showed that combination of attributes of various viruses resulted in the generation of hybrid viral vectors for efficient and targeted systemic gene therapy. We will use this strategy to generate a novel hybrid vector for targeted delivery of therapeutic genes to glioblastoma.
These approaches could result in the derivation of a targeted vector system which would represent a major advance in the management and therapy of human glioblastoma.
Technical Summary
Human malignant gliomas are highly-aggressive central nervous system tumors. The effect of current therapies is limited, and novel therapeutic approaches are required to improve the treatment of brain tumors. Gene therapy has shown early promise and presents an interesting approach for intervention; however, in brain tumor patients, efficacy has been hindered by low tumor transduction rates.
We have reported (Hajitou et al. Cell 2006) the generation of targeted hybrid prokaryotic-eukaryotic vectors, which are chimeras between two single-stranded DNA viruses, an adeno-associated virus (AAV) and targeted bacteriophage (termed AAV phage; AAVP). In our prototype, the AAV transgene cassette is inserted in an intergenomic region of the bacteriophage (phage) genome and is packaged with the phage DNA into the capsid. In addition, the vector displays the RGD 4C ligand on the phage capsid to specifically target alpha v integrin receptors overexpressed in many tumors. The combination showed improved systemic delivery and transduction for imaging and therapy.
In this application, we propose to develop a new chimeric phage-based vector for targeted delivery of therapeutic/imaging genes to angiogenic vasculature and tumor cells in brain tumors. Specifically, we will increase vector transport through the blood-brain barrier by displaying on the bacteriophage capsid ligands for transcytosis such as transferrin. Moreover, we will combine attributes of prokaryotic and eukaryotic viruses to improve endosomal escape so as to achieve superior tumor transduction. Thus, these approaches could result in the derivation of an improved targeted vector system which would represent a major advance in the management of brain tumors and the development of gene therapy systems for patient use.
We have reported (Hajitou et al. Cell 2006) the generation of targeted hybrid prokaryotic-eukaryotic vectors, which are chimeras between two single-stranded DNA viruses, an adeno-associated virus (AAV) and targeted bacteriophage (termed AAV phage; AAVP). In our prototype, the AAV transgene cassette is inserted in an intergenomic region of the bacteriophage (phage) genome and is packaged with the phage DNA into the capsid. In addition, the vector displays the RGD 4C ligand on the phage capsid to specifically target alpha v integrin receptors overexpressed in many tumors. The combination showed improved systemic delivery and transduction for imaging and therapy.
In this application, we propose to develop a new chimeric phage-based vector for targeted delivery of therapeutic/imaging genes to angiogenic vasculature and tumor cells in brain tumors. Specifically, we will increase vector transport through the blood-brain barrier by displaying on the bacteriophage capsid ligands for transcytosis such as transferrin. Moreover, we will combine attributes of prokaryotic and eukaryotic viruses to improve endosomal escape so as to achieve superior tumor transduction. Thus, these approaches could result in the derivation of an improved targeted vector system which would represent a major advance in the management of brain tumors and the development of gene therapy systems for patient use.
Organisations
People |
ORCID iD |
| Amin Hajitou (Principal Investigator) |