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A gene delivery system activatable by disease-associated matrix metalloproteinases
K W Peng1, F J Morling, F L Cosset
1Cambridge Centre for Protein Engineering, Medical Research Council Centre, UK.
Human Gene Therapy
|April 10, 1997
Summary
Developing protease-activatable gene delivery vehicles enables selective targeting of protease-expressing cells. These novel vectors show promise for gene therapy by utilizing matrix metalloproteinases (MMPs) for targeted delivery, especially in cancer and inflammation.
Area of Science:
- Biotechnology
- Gene Therapy
- Molecular Biology
Background:
- Matrix metalloproteinases (MMPs) are overexpressed in conditions like cancer, inflammation, and angiogenesis, making them therapeutic targets.
- Selective gene delivery vehicles are needed to target protease-expressing cells effectively.
Purpose of the Study:
- To engineer protease-activatable gene delivery vehicles for targeted gene delivery to protease-expressing cells.
- To investigate the role of MMPs in activating gene delivery vectors.
Main Methods:
- Engineered retroviral vectors with an epidermal growth factor (EGF) domain fused to the envelope glycoprotein via an MMP-cleavable linker.
- Tested vector binding and infectivity on cell lines with and without MMPs, using MMP inhibitors to confirm cleavage-dependent activation.
Main Results:
- The MMP-sensitive vector bound to EGF receptors but required MMP cleavage for infectivity.
- Exogenous MMPs restored infectivity of the MMP-sensitive vector on A431 cells.
- Endogenous MMPs from HT 1080 cells selectively activated the vector, resulting in a 1,000-fold higher titer compared to MMP-negative A431 cells.
Conclusions:
- Protease-activatable gene delivery vectors can be selectively activated by MMPs.
- These engineered vectors demonstrate efficient discrimination between cell types based on MMP expression, offering a promising strategy for targeted gene therapy.