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p27-p16 Chimera: a superior antiproliferative for the prevention of neointimal hyperplasia
J G McArthur1, H Qian, D Citron
1Cell Genesys, Inc., 344 Lakeside Drive, Foster City, California 94404, USA. jamesm@cellgenesys.com
Abstract:
Cyclin-dependent kinase inhibitors (CDKi's) may be useful to treat hyperproliferative vascular disorders, such as restenosis induced following angioplasty or vein engraftment. We have shown that a novel fusion protein of the CDKi's p27 and p16, named W9, significantly reduces proliferation of human coronary smooth muscle cells in vitro, by blocking cell proliferation without inducing apoptosis. We have now evaluated the efficacy of adenovirus-mediated gene transfer of W9 (AV-W9) in a balloon-injury model, in the carotid arteries of cholesterol-fed rabbits. We observed that intravascular delivery of 2 x 10(11) viral particles of AV-W9 3 days following balloon injury inhibited intimal hyperplasia by 60% compared to a control virus (P > 0.001). PCNA expression in the AV-W9-treated vessels, a marker of injury-induced cell proliferation, was also reduced compared to the control virus-treated vessels. Direct comparison of the efficacy of AV-W9 and AV-p16 and AV-p27 in this model indicated that delivery of either of the parental genes was significantly less effective in inhibiting intimal thickening compared to the AV-W9 treatment. We conclude that combining the activities of multiple cell cycle regulatory proteins greatly increases the potency of cytostatic gene therapy in the treatment of balloon injury-induced intimal hyperplasia and represents a promising potential approach to preventing postangioplasty restenosis.
Insights
A novel fusion protein W9, combining two cyclin-dependent kinase inhibitors (CDKi
Area of Science:
- Vascular Biology
- Gene Therapy
- Cardiovascular Research
Background:
- Hyperproliferative vascular disorders like restenosis pose significant clinical challenges.
- Cyclin-dependent kinase inhibitors (CDKi's) show therapeutic potential for these conditions.
- A novel fusion protein, W9 (p27/p16 CDKi's), demonstrated in vitro efficacy in reducing smooth muscle cell proliferation.
Purpose of the Study:
- To evaluate the in vivo efficacy of adenovirus-mediated W9 gene transfer (AV-W9) in a rabbit carotid artery balloon-injury model.
- To assess AV-W9's impact on intimal hyperplasia and PCNA expression post-injury.
- To compare the therapeutic effect of AV-W9 with its parental genes (AV-p16 and AV-p27).
Main Methods:
- Adenovirus-mediated gene transfer of W9 (AV-W9) was administered to balloon-injured carotid arteries in cholesterol-fed rabbits.
- Intravascular delivery of 2 x 10(11) viral particles of AV-W9 was performed 3 days post-injury.
- Intimal hyperplasia and PCNA expression were quantified and compared to control virus treatment and parental gene treatments.
Main Results:
- AV-W9 treatment inhibited intimal hyperplasia by 60% compared to the control virus (P > 0.001).
- PCNA expression, a marker of cell proliferation, was significantly reduced in AV-W9 treated vessels.
- AV-W9 demonstrated superior efficacy in inhibiting intimal thickening compared to AV-p16 or AV-p27 alone.
Conclusions:
- Combining multiple cell cycle regulatory proteins (as in W9) enhances the potency of cytostatic gene therapy.
- Adenovirus-mediated W9 gene transfer is a promising approach for preventing post-angioplasty restenosis.
- This strategy offers a potential therapeutic avenue for hyperproliferative vascular disorders.
