Researchers at Imperial College London have developed two novel modifications of bacteriophages to significantly improve their efficacy as vectors for targeted gene therapy, and exploit their advantages over eukaryotic viral vectors. These enhancements are:
- Cationic polymers, which provide a net positive charge under physiological pH, which significantly enhances the ability of the bacteriophage to perform target-specific cellular transduction.
- pIII minor coat protein which displays a cell targeting ligand (e.g. RGD4C), which enables highly targeted delivery to the target cell, for example a tumour cell.
- Recombinant and wild type pVIII major coat proteins displaying hundreds/thousands of copies of therapeutic peptides.
- enhance gene delivery by phage vectors in a targeted manner
- can be applied to overcome the major intracellular barrier to phage-mediated gene delivery by facilitating phage escape from endosomes to prevent their degradation in the lysosomes.
- in the optimal ratio with phage preserves the tumour specificity of RGD4C/phage-based gene delivery vectors while boosting the gene delivery efficacy.
pIII minor coat protein modifications:
- displays the targeting ligand for binding to a mammalian receptor.
pVIII major coat protein modifications:
- serves as a genetic carrier for foreign functional peptides to be displayed, in order to operate as a nanoparticle (nanotube) decorated by hundreds of peptides,
- allows display of large foreign peptides on the virion surface, by the recombinant pVIII protein
Lastly, the phage bears a mammalian transgene cassette inserted in an intergenomic region of the bacteriophage genome for gene expression in mammalian cells.