Rapamycin-regulated control of antiangiogenic tumor therapy following rAAV-mediated gene transfer

Area of Science:

• Gene therapy
• Molecular biology
• Oncology

Background:

• Pharmacologic control of transgene expression is crucial for gene therapy development.
• Rapamycin analogs can regulate gene expression and inhibit mTOR, offering dual therapeutic potential.
• Adeno-associated virus (AAV) vectors are promising tools for gene delivery.

Purpose of the Study:

• To develop an optimized AAV expression cassette for dimerizer-regulated gene expression.
• To evaluate the in vitro and in vivo efficacy of this regulated system.
• To assess the application of this system in controlling antiangiogenic therapy for cancer.

Main Methods:

• Construction of a recombinant AAV expression cassette for dimerizer-regulated gene expression.
• Demonstration of rapamycin-dependent transgene induction in vitro and in vivo.
• Evaluation of the system in preclinical glioblastoma models using an AAV-encoded VEGF inhibitor.

Main Results:

• The optimized AAV cassette enabled dimerizer-regulated gene expression from a single vector.
• Multiple cycles of rapamycin-dependent transgene induction were achieved in vivo.
• Regulated AAV-mediated gene transfer of a VEGF inhibitor, combined with rapamycin, significantly reduced tumor growth rates in glioblastoma models.

Conclusions:

• A novel, regulated AAV gene expression system was successfully developed.
• This system leverages rapamycin's dual function as a transcriptional inducer and mTOR inhibitor.
• The combination of this regulated AAV system with an antiangiogenic agent offers a promising therapeutic strategy for malignant diseases.