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Third-generation lentivirus vectors efficiently transduce and phenotypically modify vascular cells: implications for
Kate L Dishart1, Laura Denby, Sarah J George
1Division of Cardiovascular and Medical Sciences, University of Glasgow, Church Street, G11 6NT, Glasgow, UK.
Journal of Molecular and Cellular Cardiology
|June 24, 2003
Summary
Lentiviral vectors show promise for sustained vascular gene delivery, overcoming limitations of adenovirus and adeno-associated virus systems for treating vein graft disease. This study highlights lentivirus
Area of Science:
- Vascular Biology
- Gene Therapy
- Biomedical Engineering
Background:
- Saphenous vein grafts undergo pathological changes like medial thickening and neointima formation.
- Current gene therapy vectors like adenovirus (Ad) and adeno-associated virus serotype-2 (AAV-2) have limitations for sustained vascular gene delivery.
- Efficient and safe gene delivery is crucial for advancing vascular gene therapy to clinical applications.
Purpose of the Study:
- To evaluate alternative adeno-associated virus (AAV) serotypes and a lentiviral vector system for gene delivery to endothelial cells (ECs) and smooth muscle cells (SMCs).
- To assess the efficiency, toxicity, and sustained expression of gene delivery vectors in vascular cells.
- To demonstrate the therapeutic potential of lentiviral vectors for vascular applications.
Main Methods:
- Gene delivery to primary human saphenous vein ECs and SMCs using alternate AAV serotypes and a third-generation lentiviral vector.
- Evaluation of transduction efficiency at clinically relevant exposure times (15 min).
- Construction and overexpression of tissue inhibitor of metalloproteinase-3 (TIMP-3) using lentivirus, with assessment of transgene production, SMC migration, and cell death.
Main Results:
- Lentiviral vectors demonstrated efficient transduction of ECs and SMCs without toxicity, unlike alternate AAV serotypes which showed lower transduction compared to AAV-2.
- Transduction efficiency of lentivirus was enhanced at lower doses with Poloxamer-407 (P-407).
- Lentiviral delivery of TIMP-3 resulted in transgene production comparable to Ad, inhibiting SMC migration and inducing cell death.
Conclusions:
- Third-generation lentiviral vectors are efficient and promising for vascular gene delivery, surpassing alternate AAV serotypes.
- Lentiviral vectors offer a potential solution for sustained therapeutic gene delivery in vascular applications.
- This study establishes lentiviral vectors as a viable platform for vascular gene therapy, addressing limitations of existing systems.