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Adeno-associated virus-mediated delivery of antiangiogenic factors as an antitumor strategy
1Department of Radiological Sciences, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Abstract:
Antiangiogenic tumor therapies have recently attracted intense interest for their broad-spectrum action, low toxicity, and, in the case of direct endothelial targeting, an absence of drug resistance. To promote tumor regression and to maintain dormancy, antiangiogenic agents need to be chronically administered. Gene therapy offers a potential way to achieve sustained therapeutic release of potent antiangiogenic substances. As a step toward this goal, we have generated recombinant adeno-associated virus (rAAV) vectors that carry genes coding for angiostatin, endostatin, and an antisense mRNA species against vascular endothelial growth factor (VEGF). These rAAVs efficiently transduced three human tumor cell lines tested. Transduction with an rAAV-encoding antisense VEGF mRNA inhibited the production of endogenous tumor cell VEGF. Conditioned media from cells transduced with this rAAV or with rAAV-expressing endostatin or angiostatin inhibited capillary endothelial cell proliferation in vitro. Antiangiogenic rAAVs may offer a novel gene therapy approach to undermining tumor neovascularization and cancer progression.
Insights
Gene therapy using recombinant adeno-associated virus (rAAV) vectors delivered antiangiogenic genes. This approach successfully inhibited tumor cell growth and blood vessel formation in vitro.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Antiangiogenic therapies are crucial for tumor regression and dormancy.
- Chronic administration of antiangiogenic agents is necessary.
- Gene therapy offers sustained release of therapeutic substances.
Purpose of the Study:
- To develop recombinant adeno-associated virus (rAAV) vectors for antiangiogenic gene therapy.
- To evaluate the efficacy of rAAVs encoding angiostatin, endostatin, and anti-VEGF antisense mRNA.
- To assess the potential of this approach in inhibiting tumor neovascularization.
Main Methods:
- Generated rAAV vectors carrying genes for angiostatin, endostatin, and anti-VEGF antisense mRNA.
- Transduced three human tumor cell lines with the rAAV vectors.
- Assessed inhibition of endogenous VEGF production and capillary endothelial cell proliferation in vitro.
Main Results:
- rAAV vectors efficiently transduced human tumor cell lines.
- Transduction with anti-VEGF rAAV inhibited endogenous VEGF production.
- Conditioned media from transduced cells inhibited endothelial cell proliferation in vitro.
Conclusions:
- Antiangiogenic rAAVs represent a promising gene therapy strategy.
- This approach can potentially inhibit tumor neovascularization and progression.
- Further research into rAAV-mediated antiangiogenic therapy is warranted.